RU2672722C2 - Analogues of 4h-pyrazolo[1,5-a]benzimidazole compounds as parp inhibitors - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D is -C(R)(R) - or -N(R) -; Ris selected from the group consisting of H, Calkyl, Calkyloxy, benzyloxy and, in which Ris selected from the group consisting of H, methyl, ethyl, n-propyl or isopropyl; Ris selected from the group consisting of H, F, Cl, Br; Rsatisfies any of the following requirements (1)–(10): (1) Ris selected from H or CN; (2) Ris -CHN (R) (R), in which Rand Rare separately and independently selected from the group consisting of H, Calkyl, Calkylacyl or Ccycloalkylacyl; (3) Ris represented by heterocyclic structures denoted by groups (3a) and (3b); (4) Ris represented by structure (4a); (5) Ris represented by structure 5a; (6) Ris represented by a structure comprising (6a) or (6b); (7) Ris represented by structure (7a); (8) Ris represented by structure (8a); (9) Ris represented by structure (9a); (10) Ris represented by structure (10a), in which Tis selected from the group consisting of N or C (R); Rand Rare separately and independently selected from the group consisting of H, F, Cl, Br, I, OH; Ris selected from the group consisting of H and R; Ris Calkyl; Ris optionally substituted with R; Ris selected from the group consisting of F, Cl, Br, I, OH, N(CH), NH(CH), NH, and CHO; and the number Ris selected from 0, 1, 2 and 3.табл., 129 пр.,(3а),and(3b),(4а),(5а),(6а)and(6b),(7a),(8a),(9a),(10a).EFFECT: compounds of the invention are intended for the treatment of cancer.15 cl, 1 tbl, 129 ex

Description

FIELD OF THE INVENTION

The present invention relates to a number of analogues of 4H-pyrazolo [1,5-a] benzimidazole compounds as PARP inhibitors. More specifically, the present invention relates to compounds of formula (I) or their pharmaceutically acceptable salts as PARP inhibitors.

BACKGROUND OF THE INVENTION

PARP is a family of enzymes that catalyze the incorporation of an ADP-ribose residue into various target proteins. To date, up to 18 isoforms have been identified and characterized. Despite the large number of enzymes in the family, PARP-1 is responsible for more than 90% of ADP-ribosylation in cells.

For a long time, PARP-1 has been associated with DNA repair and maintenance of genome functioning. After DNA damage, PARP-1 is instantly activated by binding to DNA breaks. After structural changes, she begins to use NAD + for the synthesis of poly (ADB) ribose as a signal for other repair enzymes (such as DNA ligase III, DNA polymerase beta). This PARP-1 binding and activation process (known as base excision repair) enhances the repair process, which is aimed at single-stranded DNA breaks (SSB). The initiation of SSB usually occurs through oxidative damage caused by the cell’s own metabolic processes, as well as exogenous chemotherapeutic agents and radiation. It is well known that many types of anti-cancer therapeutic agents, such as DNA alkylation agents, platinum-based drugs, topoisomerase inhibitors, and radiation therapy are associated with DNA damage. The use of these therapeutic agents is overshadowed by the emergence of drug resistance, in particular in the DNA repair pathway driven by PARP-1. Recent studies have confirmed that selective PARP-1 inhibitors significantly enhance the antitumor efficacy of TMZ and cisplatin.

BRCA1 and BRCA2 play a significant role in homologous recombination (HR). DNA breaks that occur during DNA replication can only be repaired by HR. In 2005, Bryant and Farmer (Nature, 2005, 913 and 917) independently discovered that BACA1 and BACA2 deficient cell lines were very sensitive to PARP-1 inhibitors, resulting in cell death. Breast cancer genes BRCA1 / 2 have long been characterized as tumor suppressor genes, which play an integral role in the repair of double-stranded DNA breaks. Carriers of the BRCA1 / 2 mutation in ovarian and prostate cancer are also at increased risk. Therefore, PARP-1 inhibitors can also be used as a separate therapy for those types of tumors that are already devoid of certain types of DNA repair mechanism.

PARP-1 has been an actively pursued goal in oncology for 30 years and Ferraris has summarized progress in this area (J. Med. Chem. 2010, 4561). A number of compounds independently undergo clinical trials as a single agent or as a synergistically active drug, such as Veliparib (ABT-888), Niraparib (MK-4827), BMN-673, SER-977, BGP-15, E-7016, MP-124 and IND-1022. Recently, certain heterocyclic compounds have also been disclosed as being useful for treating various types of cancer in certain patent documents, for example, in WO 2014009872 (A1), WO 2014019468 (A1), WO 2014023390 (A2), WO 2013182580, WO 2013164061 (A1) EP2656843 (A1).

In addition, the inhibition of PARP-1 was an actively pursued goal of finding new drugs for a wide range of therapeutic areas, including stroke, cardiac ischemia, inflammation and diabetes (Pharmacol. Rev. 2002, 54, 375.).

Although efforts have been made all the time to develop PARP-1 inhibitors for the treatment of cancer and other diseases, satisfactory treatment has not yet been achieved. Thus, there is a need for the development of new PARP-1 inhibitors.

SUMMARY OF THE INVENTION

An object of the present invention is to provide compounds represented by formula (I), or pharmaceutically acceptable salts thereof,

Where

D is selected from the group consisting of -C (R _d1 ) (R _d2 ) -, -C (= O) N (R _d3 ) -, -N (R _d4 ) -, -C (= NR _d5 ) -, -S (= O) ₂ N (R _d6 ) -, -S (= O) N (R _d7 ) -, -O-, -S-, -C (= O) O-, -C (= O) -, -C (= S) -, -S (= O) - or -S (= O) ₂ -;

R _1-3 , R _d1 and R _{d2 are} separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH and NH ₂ , or selected from the group consisting of optionally substituted R ₀₁ C _{1- 10} alkyl, C _1-10 heteroalkyl, C _3-10 halohydrocarbyl, C _3-10 heterocyclohydrocarbyl, C _1-10 alkyl substituted with C _3-10 cyclohydrocarbyl or C _3-10 heterocyclohydrocarbyl, and C _1-10 heteroalkyl substituted with C _{3 -10} cyclohydrocarbyl or C _3-10 heterocyclohydrocarbyl.

R _{01 is} selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH _2, and R ₀₂ ;

R _{02 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylamino, N, N-di (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkylacyl, C _1-10 alkyloxycarbonyl , C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 dicloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl;

the heteroatom or heteroatomic group is individually and independently selected from the group consisting of —C (= O) N (R _d3 ) -, —N (R _d4 ) -, —C (= NR _d5 ) -, —S (= O) ₂ N (R _d6 ) -, -S (= O) N (R _d7 ) -, -O-, -S-, -C (= O) O-, -C (= O) -, -C (= S) -, -S (= O) - and -S (= O) ₂ -;

R _d3 - _{d7 are} separately and independently selected from the group consisting of H and R ₀₃ ;

R _{03 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkyloxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _3-10 dicloalkylsulfinyl;

R ₀₂ and R _{03 are} optionally substituted with R ₀₀₁ ;

R _{001 is} selected from the group consisting of F, Cl, Br, I, CN, OH, N (CH ₃ ) ₂ , NH (CH ₃ ), NH ₂ , CF ₃ , (NH ₂ ) CH ₂ , (HO) CH ₂ , CH ₃ , CH ₃ O, HC (= O), CH ₃ OC (= O), CH ₃ S (= O) ₂ and CH ₃ S (= O); and

the number of R ₀₁ , R ₀₀₁ heteroatoms or heteroatom groups is individually and independently selected from 0, 1, 2 or 3.

In one embodiment of the present invention, D is selected from —NH—, —N (CH ₃ ) -, —C (F) ₂ -, —C (H) (F) -, and —C (H) (OH) -.

,

и

, при этомIn one embodiment of the present invention, R _{1-3 is} separately and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-6 alkyl, C _1-6 alkyloxy, benzyloxy , -CH ₂ N (R ₂₁ ) (R ₂₂ ),

,

and

, wherein

L and D _{21 are} separately and independently selected from the group consisting of -C (R _d1 ) (R _d2 ) -, -C (= O) N (R _d3 ) -, -N (R _d4 ) -, -C (= NR _d5 ) -, -S (= O) ₂ N (R _d6 ) -, -S (= O) N (R _d7 ) -, -O-, -S-, -C (= O) -, -C ( = O) O-, -C (= S) -, -S (= O) - or -S (= O) ₂ -;

L may also be a single bond solely for the purpose of binding;

T ₂₁ - ₂₂ separately and independently selected from the group comprising C (R _t ) and N;

X is selected from (CH ₂ ) _n optionally substituted with R ₀₁ , and n is selected from 0, 1, 2, or 3, and preferably from 0, 1, or 2;

Y is selected from (CH ₂ ) _m optionally substituted with R ₀₁ , am is selected from 0, 1, 2, or 3, and preferably from 1, 2, or 3;

R _21-23 and R _d3 - _{d7 are} separately and independently selected from the group consisting of H and R ₀₃ ;

R _24-27 , R _d1 , R _d2 and R _{t are} individually and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, and NH ₂ , or selected from the group consisting of optionally substituted R ₀₁ C _1-10 alkyl, C _1-10 heteroalkyl, C _3-10 cyclohydrocarbyl, C _3-10 heterocyclohydrocarbyl, C _1-10 alkyl substituted with C _3-10 cyclohydrocarbyl or C _3-10 heterocyclohydrocarbyl, and C _1-10 heteroalkyl substituted with C _3-10 cyclohydrocarbyl or C _3-10 heterocyclohydrocarbyl;

R _{01 is} selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH _2, and R ₀₂ ;

R _{02 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylamino, N, N-di (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkylacyl, C _1-10 alkyloxycarbonyl , C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl; a heteroatom or heteroatomic group separately and are independently selected from the group consisting of -C (= O) N (R d3) -, -N (R d4) -, -C (= NR d5) -, -S (= O) ₂ N (R _d6 ) -, -S (= O) N (R _d7 ) -, -O-, -S-, -C (= O) O-, -C (= O) -, -C (= S) -, -S (= O) - and / or -S (= O) ₂ -;

R _d3 - _{d7 are} separately and independently selected from the group consisting of H and R ₀₃ ;

R _{03 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkyloxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl;

R ₀₂ and R _{03 are} optionally substituted with R ₀₀₁

R _{001 is} selected from the group consisting of F, Cl, Br, I, CN, OH, N (CH ₃ ) ₂ , NH (CH ₃ ), NH ₂ , CF ₃ , (NH ₂ ) CH ₂ , (HO) CH ₂ , CH ₃ , CH ₃ O, HC (= O), CH ₃ OC (= O), CH ₃ S (= O) ₂ and CH ₃ S (= O); and

the amount of R ₀₁ , R ₀₀₁ , a heteroatom or a heteroatom group is individually and independently selected from 0, 1, 2 or 3.

, в котором R₁₀₁ выбран из группы, включающей Н, метил, этил, н-пропил или изопропил.In one embodiment of the present invention, R ₁ and R _{3 are} individually and independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-3 alkyl, C _1-3 alkyloxy, benzyloxy and

wherein R _{101 is} selected from the group consisting of H, methyl, ethyl, n-propyl or isopropyl.

и

.In one embodiment of the present invention, R _{1 is} selected from the group consisting of H, methyl, methyloxy, benzyloxy,

and

.

In one embodiment of the present invention, R _{3 is} selected from the group consisting of H, F, Cl, Br, CN, and methyl.

In one embodiment of the present invention, R _{2 is} selected from —CH ₂ N (R ₂₀₁ ) (R ₂₀₂ ), wherein R ₂₀₁ and R _{202 are} individually and independently selected from the group consisting of H, C _1-3 alkyl, C _1-3 alkylacyl, C _3-6 cycloalkylacyl or C _3-6 cycloalkyl.

In one embodiment of the present invention, R ₂₀₁ and R _{202 are} individually and independently selected from the group consisting of H or cyclopropylacyl.

и

.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

.

и

, в которых R₂₀₃, R₂₀₄, R₂₁₇ и R₂₁₈ отдельно и независимо выбраны из группы, включающей Н, замещенный или незамещенный С_1-3алкил, циклопропил или циклопропилметилен, где заместитель выбран из группы, включающей F, Cl, Br, I, CN, ОН, NH₂, метил или метилоксил, а количество заместителей составляет 0, 1, 2 или 3.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

in which R ₂₀₃ , R ₂₀₄ , R ₂₁₇ and R _{218 are} individually and independently selected from the group consisting of H, substituted or unsubstituted C _1-3 alkyl, cyclopropyl or cyclopropylmethylene, where the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyl or methyloxy, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R _{203 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, —CH ₂ C (CH ₃ ) (CH ₃ ) (OH), and cyclopropylalkylene.

In one embodiment of the present invention, R _{204 is} selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

In one embodiment of the present invention, R _{217-219 are} individually and independently selected from the group consisting of methyl and ethyl.

и

.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

.

, в котором R₂₀₅ и R₂₀₆ отдельно и независимо выбраны из группы, включающей Н, замещенный или незамещенный С_1-3алкил, циклопропил или циклопропилметилен, где заместитель выбран из группы, включающей F, Cl, Br, I, CN, ОН, NH₂, метил или метилоксил, а количество заместителей составляет 0, 1, 2 или 3.In one embodiment of the present invention, R _{2 is} selected from

in which R ₂₀₅ and R _{206 are} individually and independently selected from the group consisting of H, substituted or unsubstituted C _1-3 alkyl, cyclopropyl or cyclopropylmethylene, where the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyl or methyloxy, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R ₂₀₅ and R _{206 are} separately, independently and preferably selected from the group consisting of H, methyl, ethyl, n-propyl and isopropyl, and R _{206 is} also preferably selected from the group comprising F, Cl, Br, I , CN, OH and NH ₂ .

.In one embodiment of the present invention, R _{2 is} selected from

.

и

.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

.

, в котором R₂₀₇ выбран из группы, включающей Н, замещенный или незамещенный С_1-3алкил, циклопропил, циклопропилметилен, циклобутил, циклобутилметилен, оксациклобутил или оксациклобутилалкилен, где заместитель выбран из группы, включающей F, Cl, Br, I, CN, ОН, NH₂, метил, CF₃, метилоксил и метилсульфонил, а количество заместителей составляет 0, 1, 2 или 3.In one embodiment of the present invention, R _{2 is} selected from

wherein R _{207 is} selected from the group consisting of H, substituted or unsubstituted C _1-3 alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, oxacyclobutyl or oxacyclobutylalkylene, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyl, CF ₃ , methyloxy and methylsulfonyl, and the number of substituents is 0, 1, 2 or 3.

,

и

.In one embodiment of the present invention, R _{207 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, —CH ₂ CF ₃ , —CH ₂ CH ₂ CF ₃ , —CH ₂ CH ₂ F, —CH ₂ CH ₂ S (= O) ₂ CH ₃ , -CH ₂ CH ₂ CN,

,

and

.

и

.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

.

или

, в которых R₂₀₈ выбран из группы, включающей Н, замещенный или незамещенный С_1-4алкил, где заместитель выбран из группы, включающей F, Cl, Br, I, CN, ОН, NH₂, метил, CF₃, метилоксил и метилсульфонил, а количество заместителей составляет 0, 1, 2 или 3.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

or

in which R _{208 is} selected from the group consisting of H, substituted or unsubstituted C _1-4 alkyl, where the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyl, CF ₃ , methyloxy and methylsulfonyl, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R _{208 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene and cyclobutyl.

и

.In one embodiment of the present invention, R _{2 is} selected from the group consisting of

and

.

, в котором R₂₀₉ выбран из группы, включающей -C(R_d1)(R_d2)-, C(=O)N(R_d3)-, -N(R_d4)-, -C(=NR_d5)-, -S(=O)₂N(R_d6)-, -S(=O)N(R_d7)-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- или -S(=O)₂-, где R_d1-d7 представляют собой таковые, определенные в п. 1.In one embodiment of the present invention, R _{2 is} selected from

in which R _{209 is} selected from the group consisting of -C (R _d1 ) (R _d2 ) -, C (= O) N (R _d3 ) -, -N (R _d4 ) -, -C (= NR _d5 ) - , -S (= O) ₂ N (R _d6 ) -, -S (= O) N (R _d7 ) -, -O-, -S-, -C (= O) O-, -C (= O ) -, -C (= S) -, -S (= O) - or -S (= O) ₂ -, where R _d1-d7 are those defined in paragraph 1.

In one embodiment of the present invention, R _{209 is} selected from the group consisting of O and S (= O) ₂ .

, в котором R₂₁₀ выбран из группы, включающей Н, F, Cl, Br, I, CN, ОН, SH, NH₂, N,N-ди(С_1-3алкил)амино и С_1-3алкиламино.In one embodiment of the present invention, R _{2 is} selected from

wherein R _{210 is} selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH ₂ , N, N-di (C _1-3 alkyl) amino and C _1-3 alkylamino.

In one embodiment of the present invention, R _{210 is} selected from the group consisting of dimethylamino, methylamino, H, F, Cl, Br, I, CN, OH, and NH ₂ .

, в котором R_211-214 выбраны из группы, включающей Н или замещенный или незамещенный С_1-4алкилоксилкарбонил, С_1-4алкил, 3-6-членный циклоалкил, 3-6-членный циклоалкилметилен или ненасыщенный 5-6-членный гетероциклогидрокарбил, где заместитель включает R₂₁₅, и R_211-213 также выбраны из группы, включающей Н, F, Cl, Br, I, CN, ОН и NH₂, при этом циклоалкил или ненасыщенный гетероциклогидрокарбил содержит О, S или NR₂₁₆ в количестве 0, 1 или 2, гдеIn one embodiment of the present invention, R _{2 is} selected from

wherein R _{211-214 is} selected from the group consisting of H or substituted or unsubstituted C _1-4 alkyloxycarbonyl, C _1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkylmethylene, or unsaturated 5-6 membered heterocyclehydrocarbyl wherein the substituent includes R ₂₁₅ and R _{211-213 are} also selected from the group consisting of H, F, Cl, Br, I, CN, OH and NH ₂ , wherein cycloalkyl or unsaturated heterocyclohydrocarbyl contains O, S or NR ₂₁₆ in an amount 0, 1 or 2, where

R _{216 is} selected from the group consisting of H and C _1-4 alkyl, substituted with R ₂₁₅ ,

R _{215 is} selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, methyloxy, ethyloxy, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methyloxycarbonyl, ethyloxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylamine oxo

the amount of R ₂₁₅ is 1, 1, 2 or 3,

optionally R ₂₁₂ and R ₂₁₃ can be combined together to form a linker selected from the group consisting of —CH ₂ -, —CH ₂ CH ₂ -, or —CH ₂ CH ₂ CH ₂ -;

In one embodiment of the present invention

R _{211 is} selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, hydroxylmethyl and methyloxycarbonyl,

R _{212 is} selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH ₂ and methyl,

R _{213 is} selected from the group consisting of H, F, Cl, Br, I, CN, OH, and NH ₂ ,

циклопропил, циклопропилметилен,

и

;R _{214 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CH ₂ C (OH) (CH ₃ ) ₂ , —CH ₂ C (F) ( CH ₃ ) ₂ , -CH ₂ CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) ₂ , -S (= O) ₂ CH ₃ , -CH ₂ CH ₂ S (= O) ₂ CH ₃

cyclopropyl, cyclopropylmethylene,

and

;

In one embodiment of the present invention, R _{2 is} selected from the group consisting of

и

and

, в котором Т₂₂ выбран из группы, включающей N или C(R₂₂₄), а R_220-224 отдельно и независимо выбраны из группы, включающей Н, F, Cl, Br, I, CN, ОН, SH, NH₂, С_1-3алкиламино-С_1-3алкил и

.In one embodiment of the present invention, R _{2 is} selected from

in which T _{22 is} selected from the group comprising N or C (R ₂₂₄ ), and R _{220-224 is} separately and independently selected from the group comprising H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-3 alkylamino-C _1-3 alkyl and

.

In one embodiment of the present invention, C _1-3 alkylamino-C _1-3 alkyl is selected from methylaminomethylene.

In one embodiment of the present invention

и

.R ₂ is selected from the group consisting of

and

.

In one embodiment of the present invention, the compounds or pharmaceutically acceptable salts thereof are selected from

1) 6-fluoro-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

2) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

3) 6-fluoro-3- (1- (2-fluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

4) 3- (1-cyclopropylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

5) 3- (1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

6) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

7) 6-fluoro-3- (1- (2-fluoro-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

8) 3- (1- (cyclopropylcarbonyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

9) 6-fluoro-3- (1-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

10) 6-fluoro-3- (1-isopropylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

11) 6-fluoro-3- (1- (oxetan-3-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

12) 6-fluoro-3- (1-propylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

13) 3- (1- (2-aminoethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

14) 3- (1- (2- (dimethylamino) ethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

15) 6-fluoro-3- (1- (2-methoxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

16) 6-fluoro-3- (1- (2-hydroxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

17) 3- (1-ethylpiperidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

18) 3- (1-ethylazepan-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

19) 6-fluoro-3- (1-methylazepan-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

20) 6-fluoro-3- (1-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

21) 3- (1-ethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

22) 6-fluoro-3- (1-isopropylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

23) 6-fluoro-3- (pyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

24) 6-fluoro-3- (1-propylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 6-fluoro-3- (1-methylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

25) 3- (1-ethylpyrrolidin-2-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

26) 3- (1-ethylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

27) 6-fluoro-3- (3-methyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

28) 3- (3-ethyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

29) 3- (3-cyclobutyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

30) 3- (3- (cyclopropylmethyl) -3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide;

31) 6-fluoro-3- (3-isopropyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

32) 3- (3-azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

33) 3- (3-ethyl-3-azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

34) 3- (8-ethyl-8-azabicyclo [3.2.1] octan-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

35) 6-fluoro-3- (4-hydroxypyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

36) 3-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

37) 3-cyano-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

38) 3- (aminomethyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

39) 3- (cyclopropanecarboxamidomethylene) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

40) 6-fluoro-3- (4-fluorophenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

41) 6-fluoro-3- (2-fluoro-4 - ((methylamino) methylene) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

42) 6-fluoro-3- (4 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

43) 6-fluoro-3- (2-fluoro-5 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

44) 6-fluoro-3- (pyridin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

45) 6-fluoro-3- (4- (piperidin-3-yl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

46) 6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

47) 3- (4- (dimethylamino) cyclohexyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

48) 6-fluoro-3- (4-methylpiperazine-1-carbonyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

49) 3- (1- (cyclopropylmethyl) piperidin-4-yl) -4,4,6-trifluoro-4H-pyrazolo [1,5-a] indole-8-carboxamide;

50) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4-hydroxy-4H-pyrazolo [1,5-a] indole-8-carboxamide;

51) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

52) 6-fluoro-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

53) 3- (1-ethyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

54) 3- (1-cyclopropyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

55) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide;

56) 3- (1- (cyclopropylmethylene) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

57) 3- (1- (4,4-difluorocyclohexyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

58) 6-fluoro-3- (4-methyl-1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide;

59) 6-fluoro-3- (1- (2-fluoroethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

60) 6-fluoro-3- (4-methyl-1- (2,2,2-trifluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide;

61) 6-fluoro-3- (4-methyl-1- (3,3,3-trifluoropropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide;

62) 3- (1 - ((1-cyanocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

63) 3- (1 - ((1-cyanocyclobutyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

64) 6-fluoro-3- (4-methyl-1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide;

65) 6-fluoro-3- (4-methyl-1 - ((tetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2- b] pyrazole-8-carboxamide;

66) 3- (1 - ((1-aminocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

67) 6-fluoro-3- (4-methyl-1- (oxetan-3-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

68) 6-fluoro-3- (1- (2-methoxyethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

69) 6-fluoro-3- (1 - ((1-hydroxycyclopropyl) methyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

70) 6-fluoro-3- (4-methyl-1 - ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

71) 6-fluoro-3- (1- (3-methoxypropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

72) 6-fluoro-3- (4-methyl-1 - ((1- (methylsulfonyl) cyclopropyl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide;

73) 6-fluoro-3- (4-methyl-1- (thiazol-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

74) 6-fluoro-3- (4-methyl-1- (methylsulfonyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

75) 6-fluoro-3- (1- (3-fluorocyclobutyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

76) 6-fluoro-3- (4-methyl-1- (thiophen-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

77) 3- (1 - ((1-ethylpiperidin-4-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide;

78) 6-fluoro-3- (4-methyl-1 - ((1-methylazetidin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

79) ethyl-2 - ((4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-yl) methyl) cyclopropanecarboxylate;

80) 3- (1 - ((2- (dimethylcarbamoyl) cyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide;

81) 6-fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

82) 6-fluoro-3- (4-methyl-1 - ((4-methylthiazol-5-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

83) 6-fluoro-3- (4-methyl-1 - ((1-methyl-1H-imidazol-2-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1, 2-b] pyrazole-8-carboxamide;

84) 3- (1 - ((1,2-dimethyl-1H-imidazol-5-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1 , 2-b] pyrazole-8-carboxamide;

85) 3- (1'-ethyl-4-methyl- [1,4'-bipiperidin] -4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide;

86) 6-fluoro-3- (4-methyl-1 - ((6-oxo-1,6-dihydropyridazin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [ 1,2-b] pyrazole-8-carboxamide;

87) 3- (1- (2-cyanoethyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

88) 6-chloro-3- (1-ethyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

89) 3- (1-ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

90) 3- (1,3-Dimethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

91) 6-fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

92) 3- (1- (cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

93) 6-fluoro-3- (3-methyl-1- (oxetan-3-yl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

94) 6-fluoro-3- (1- (2-fluoroethyl) -3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

95) 3- (1 - ((2,2-difluorocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide;

96) 6-fluoro-3- (3-methyl-1- (2,2,2-trifluoroethyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide;

97) 6-fluoro-3- (3-methyl-1- (2- (methylsulfonyl) ethyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide;

98) 6-fluoro-3- (3-methyl-1- (3,3,3-trifluoropropyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide;

99) 3- (1 - ((1-aminocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

100) 3- (1 - ((1-cyanocyclobutyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

101) 3- (1 - ((1-cyanocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ;

102) 3- (1- (2-cyanoethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

103) 3- (1- (cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

104) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

105) 6-fluoro-3- (4-methyl-1,1-dioxo-2H-thiopyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

106) 3- (1,4-diethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

107) 3- (4-cyano-1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

108) 3- (1- (cyclopropylmethyl) -4- (hydroxymethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

109) methyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -1- (cyclopropylmethyl) piperidine-4-carboxylate;

110) 3- (1- (cyclopropylmethyl) -4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

111) 3- (1-ethyl-4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

112) 6-fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

113) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

114) 3- (1,4-dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

115) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

116) 3- (1-ethyl-2,4-dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

117) 3- (1-ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

118) 6-fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

119) 3- (1- (cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

120) 3- (1,3-dimethylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

121) 3- (1-ethyl-3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

122) 6-fluoro-3- (1-isopropyl-3-methylazetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

123) 3- (1- (cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

124) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -3-methylazetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

125) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

126) 2- (benzyloxy) -6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

127) 6-fluoro-2- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide;

128) 2- (1-ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide.

DEFINITIONS

C _{1-10 is} selected from the group consisting of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ; C _{3-10 is} selected from the group consisting of C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C _9, and C ₁₀ .

C _1-10 alkyl, C _1-10 heteroalkyl, C _3-10 cyclohydrocarbyl, C _3-10 heterocyclohydrocarbyl, C _1-10 alkyl substituted with C _3-10 cyclohydrocarbyl or C _3-10 heterocyclohydrocarbyl, or C _1-10 heteroalkyl, substituted C _3-10 or C _3-10 tsiklogidrokarbilom geterotsiklogidrokarbilom include without limitation

C _1-10 alkyl, C _1-10 alkylamino, N, N-di (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkylacyl, C _1-10 alkyloxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _{3 -10} cycloalkylsulfinyl;

methyl, ethyl, n-propyl, isopropyl, -CH ₂ C (CH ₃ ) (CH ₃ ) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropylacyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxylmethyl, methyloxy, formyl, methyloxycarbonyl, methylsulfonyl, methylsulfinyl, ethyloxy, acetyl, ethylsulfonyl, ethyloxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl and diethylaminocarbonyl;

- CH₂CH(OH)(CH3)₂, -CH₂CH(F)(CH₃)₂, -CH₂CH₂F, -CH₂CF₃, -CH₂CH₂CF₃, -CH₂CH₂NH₂, -CH₂CH₂OH, -CH₂CH₂OCH₃, -CH₂CH₂CH₂OCH₃, -CH₂CH₂N(CH₃)₂, -S(=O)₂CH₃, CH₂CH₂S(=O)₂CH₃,

,

N (CH ₃ ) ₂ , NH (CH ₃ ), -CH ₂ CF ₃ , -CH2CH ₂ CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ S (= O) ₂ CH ₃ , CH ₂ CH ₂ CN

- CH ₂ CH (OH) (CH3) ₂ , -CH ₂ CH (F) (CH ₃ ) ₂ , -CH ₂ CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) ₂ , -S (= O) ₂ CH ₃ , CH ₂ CH ₂ S (= O) ₂ CH ₃ ,

,

и

and

phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolynyl, pyrrolidinyl, 1,3-oxolanyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2 , 3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5 -tritianil, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl or quinoxalinyl.

The term “pharmaceutically acceptable” is used herein to refer to such compounds, materials, compositions and / or dosage forms which, in the framework of sound medical judgment, are suitable for use with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications according to a reasonable benefit / risk ratio.

The term “pharmaceutically acceptable salt” is intended to include a salt of a compound of the present invention, which is prepared using a relatively non-toxic acid or base and a compound of the present invention having specific substituents. If the compound of the present invention contains a relatively acidic functional group, then the base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the necessary base, either in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like. If the compound of the present invention contains a relatively basic functional group, then the acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids, including hydrochloric, hydrobromic, nitric, carbonic, hydrocarbonic, phosphoric, hydrophosphoric, dihydrophosphoric, sulfuric, hydrogen sulfide, hydroiodic or phosphorous acids and the like; as well as salts of organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, cork, fumaric, lactic, almond, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic acid or the like. ; as well as salts of amino acids (such as arginate and the like) and salts of organic acids such as glucuronic acid and the like. (see Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups that enable the conversion of the compounds to either base addition salts or acid addition salts.

The neutral form of this compound is preferably regenerated by contacting the salt with a base or acid, followed by isolation of the starting compound in the usual manner. The initial form of the compound differs from the various forms of its salts in certain physical properties, such as solubility in polar solvents.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present invention, wherein the parent compound is modified by preparing a salt with an acid or base. Examples of pharmaceutically acceptable salts include, without limitation, salts of a mineral or organic acid with basic groups such as amines; alkali or organic salts with acidic groups such as carboxylic acids; etc. Pharmaceutically acceptable salts include the usual non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarboxylic, carbonic, citric, ethylenediaminetetraacetic, ethanedisulfonic, ethanesulfonic, fumefurton gluconic, glutamic, glycolic, hydrobromic, hydrochloric, hydroiodic, hydroxy acids, hydroxy naphthoic, isethionic, lactic, lactobionic, lauryl ulfonovoy, maleic, malic, mandelic, methanesulfonic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, peracetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety through conventional chemical methods. Typically, such salts can be prepared by reacting the free forms of the acid or base of these compounds with a stoichiometric amount of the corresponding base or acid in water, or in an organic solvent, or a mixture thereof; typically a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or the like. are preferred.

In addition to salt forms, the present invention provides compounds that are in the form of a prodrug. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the present invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms are similar to unsolvated forms and all are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.

Certain compounds of the present invention may contain asymmetric carbon atoms (optical centers) or double bonds; however, all racemates, diastereomers, geometric isomers and individual isomers are included in the scope of the present invention.

The graphical representations of racemic, ambiscalemic, and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Continuous and intermittent wedges are used to indicate the absolute configuration of the stereo center, unless otherwise indicated. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is understood that the compounds include both E and Z geometric isomers. Similarly, all tautomeric forms are included in the scope of the present invention.

The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereomers, (D) isomers, (L) -isomers, their racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, and all these mixtures, which are included in the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

Optically active (R) - and (S) -isomers and D- and L-isomers can be obtained by chiral synthons, or chiral reagents, or other conventional techniques. If a specific enantiomer of a compound of the present invention is needed, it can be obtained by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to give the pure desired enantiomers. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acid functional group (such as a carboxyl group), then diastereomeric salts can be formed with the corresponding optically active acid or base, followed by cleavage of the diastereomers by fractional crystallization or chromatographic methods known in the art and subsequent reduction of the pure enantiomers. In addition, the separation of enantiomers and diastereomers is often carried out by chromatography using chiral stationary phases, optionally in combination with chemical derivatization (for example, the formation of carbamates from amines).

The compounds of the present invention may also contain unusual ratios of atomic isotopes on one or more atoms that make up such compounds. For example, the compounds may be radiolabelled, such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, despite their radioactivity, are intended to be included in the scope of the present invention.

The term “pharmaceutically acceptable carrier or excipient” refers to any composition or carrier medium that is capable of delivering an effective amount of the active agent of the present invention without toxic side effects with respect to the host or patient. Illustrative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their composition is well known to specialists in the field of cosmetics and pharmaceuticals for external use. Further information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term “adjuvant” usually means carriers, diluents and / or excipients necessary for the preparation of effective pharmaceutical compositions.

The terms "effective amount" or "therapeutically effective amount" in relation to a drug or pharmacologically active agent refers to a non-toxic, but sufficient amount of the drug or pharmacologically active agent to provide the desired effect. In the oral dosage forms of the present disclosure, an “effective amount” of an active agent of a composition refers to the amount of active agent necessary to provide the desired effect when used in combination with another active agent of the composition. The amount that is "effective" will vary between subjects depending on the age and general condition of the recipient, as well as the specific active agent, and the corresponding effective amount in a particular case can be determined by a specialist of average skill in this field using a routine experiment.

The terms “active ingredient”, “therapeutic agent”, “active substance” or “active agent” mean a chemical entity that may be effective in treating a target disorder, disease or condition.

The term “substituted” means that any one or more hydrogen atoms at the specified atom is substituted with a substituent, including deuterium and a variant of hydrogen, provided that the valency of the specified atom is normal and that the substituted compound is stable. If the substituent is a ketone group (i.e., = O), then this means that 2 hydrogen atoms are substituted. Keto substituents are not present in aromatic moieties. The term “optionally substituted” means that the specified atom may be substituted or not substituted and, unless otherwise indicated, the types and number of substituents can be arbitrary, provided that they can be obtained in chemistry.

If a variable (for example, R) occurs more than once in a component or structure of a compound, then its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, then said group may optionally be substituted by no more than two R groups, with R in each case having independent variants. In addition, combinations of substituents and / or variables are permissible only if such combinations provide stable compounds.

If it is shown that a bond with a substituent crosses a bond connecting two atoms in a ring, then such a substituent can be bound to any atom in the ring. If a substituent is shown without indicating by which atom such a substituent is bonded to a compound of the general formula, including unspecified compounds, then such a substituent can be bonded via any atom in the compound. Combinations of substituents and / or variables are permissible only if such combinations provide stable compounds.

Substituents of alkyl and heteroalkyl radicals (including those groups that are often called alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) are usually referred to as “substituents of the alkyl group” and one or more of the following can be selected : -R ', -OR', = O, = NR ', = N-OR', -NR'Rʺ, -SR ', -halogen, -SiR'RʺR''', OC (O) R ', - C (O) R ', -CO ₂ R', -CONR'R", -OC (O ) NR'R", -NR"C (O) R ', NR'C (O) NR"R"', -NR"C (O) ₂ R ', -NRʺ'ʺ-C (NR'RʺRʺ') = NRʺʺ, NRʺʺC (NR'Rʺ) = NR'ʺ, -S (O) R ', -S (O) ₂ R', -S (O ) ₂ NR'Rʺ, NRʺSO ₂ R ', -CN, -NO ₂ , -N ₃ , -C H (Ph) ₂ and fluoro (C ₁ -C ₄ ) alkyl, with the number of substituents ranging from zero to (2m ′ + 1), where m ′ represents the total number of carbon atoms in such a radical. Each of R ', Rʺ, Rʺ', Rʺʺ and Rʺʺ 'is preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy- groups or aryl alkyl groups. If the compound of the present invention includes, for example, more than one group R, then each of the groups R is independently selected, as well as each of the groups R ', Rʺ, Rʺ', Rʺʺ and Rʺ'ʺ, if more than one of these groups is present. If R ′ and Rʺ are attached to the same nitrogen atom, then they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'Rʺ is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups consisting of carbon atoms bonded to groups other than hydrogen groups such as haloalkyl (e.g., -CF ₃ and -CH ₂ CF ₃ ) and acyl (e.g., -C (O) CH ₃ , -C (O) CF ₃ , -C (O) CH ₂ OCH ₃ , etc.).

Like substituents described for an alkyl radical, substituents of aryl and heteroaryl groups are generally referred to as “substituents of the aryl group”. The substituents are selected, for example, from the following: -R ', -OR', -NR'Rʺ, -SR ', -halogen, -SiR'RʺRʺ', OC (O) R ', -C (O) R', - CO ₂ R ', -CONR'Rʺ, -OC (O) NR'Rʺ, -NRʺC (O) R', NR'C (O) NRʺRʺ ', -NRʺC (O) ₂ R', -NRʺʺ'-C (NR'RʺRʺ ') = NRʺʺ, NRʺʺC (NR'Rʺ) = NRʺ', -S (O) R ', -S (O) ₂ R', -S (O) ₂ NR'Rʺ, NRʺSO ₂ R ' , —CN, —NO ₂ , —N ₃ , —CH (Ph) ₂ , fluoro (C ₁ -C ₄ ) alkoxy and fluoro (C ₁ -C ₄ ) alkyl, etc., with the number of substituents varying from zero to the total number of open valencies in the aromatic ring; where each of R ', Rʺ, R'ʺ, Rʺʺ and R'ʺʺ is preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. If the compound of the present invention includes, for example, more than one R group, then each of the R groups is independently selected as well as each of the groups R ', Rʺ, R'ʺ, Rʺʺ and Rʺʺ' if more than one of these groups is present.

Two substituents at adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -TC (O) - (CRR ') qU-, where T and U are independently selected from -NR-, -O-, -CRR'- or a single bond , aq is an integer from 0 to 3. Alternatively, two substituents at adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -A (CH ₂ ) rB-, where A and B are independently selected from -CRR'-, -O-, -NR-, -S-, -S (O) -, S (O) ₂ -, -S (O) ₂ NR'- or a single bond, and r is an integer from 1 to 4. One from single bonds arr thus the new call of the ring may optionally be substituted with a double bond. Alternatively, two substituents at adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula —A (CH ₂ ) rB—, where s and d are individually and independently selected from integers from 0 to 3, and X represents —O -, -NR'-, -S-, -S (O) -, -S (O) ₂ - or -S (O) ₂ NR'-. The substituents R, R ', Rʺ and R'ʺ are individually, preferably and independently selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ ) alkyl.

The term “hydrocarbyl” or its hyponyms (such as alkyl, alkenyl, alkynyl and phenyl, etc.) by themselves or as part of another substituent means, unless otherwise indicated, a straight or branched chain, or a cyclic hydrocarbon radical, or a combination thereof which may be fully saturated, mono- or polyunsaturated, and can be mono-, di- or multiply substituted and can include di- and multivalent radicals, having the specified number of carbon atoms (e.g., C ₁ to C _10, which means one up to ten carbon atoms). “Hydrocarbyl” includes, without limitation, aliphatic hydrocarbyl and aromatic hydrocarbyl, while aliphatic hydrocarbyl includes linear and cyclic hydrocarbyls, in particular, including without limitation alkyl, alkenyl and alkynyl, and aromatic hydrocarbyl includes, without limitation, 6-12 membered aromatic hydrocarbyl, for example benzene, naphthalene, etc. In some embodiments, the term “alkyl” means a straight or branched chain radical, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and may include di- and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologues and isomers of radicals such as n pentyl, n-hexyl, n-heptyl, n-octyl and the like. An unsaturated alkyl group is a group having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1st 3- propynyl, 3-butynyl and higher homologues and isomers.

The term “heterohydrocarbyl” or its hyponyms (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) alone or in combination with another term means, unless otherwise indicated, a stable straight or branched chain, or a cyclic hydrocarbon radical, or combinations comprising the indicated number of carbon atoms and at least one heteroatom. In some embodiments, the term “heteroalkyl” alone or in combination with another term means a straight or branched chain stable hydrocarbon radical or combinations thereof comprising the indicated number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) B, O, N and S can be located in any internal position of the heterohydrocarbyl group (except for the position in which the hydrocarbyl group is attached to the remainder of the molecule). Examples include, but are not limited to —CH ₂ —CH ₂ —O — CH ₃ , —CH ₂ —CH ₂ —NH — CH ₃ , —CH ₂ —CH ₂ —N (CH ₃ ) —CH ₃ , —CH ₂ —S— CH ₂ —CH ₃ , —CH ₂ —CH ₂ , —S (O) —CH ₃ , —CH ₂ —CH ₂ —S (O) ₂ —CH ₃ , —CH = CH — O — CH ₃ , —CH ₂ -CH = N-OCH ₃ and -CH = CH-N (CH ₃₎ -CH _3. No more than two heteroatoms can follow each other, such as, for example, —CH ₂ —NH — OCH ₃ .

The terms “alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy) are used in their usual meaning and refer to such alkyl groups that are attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively.

The terms “cyclohydrocarbyl”, “heterocyclohydrocarbyl” or “cyclohydrocarbylheteroyl” or their hyponyms (such as aryl, heteroaryl, arylheteroyl, cycloalkyl, heterocycloalkyl, cycloalkyl heteroalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, denote, unless otherwise indicated, cyclic variants of "hydrocarbyl", "heterohydrocarbyl" or "hydrocarbylheteroil", respectively. In addition, For heterohydrocarbyl or heterocyclohydrocarbyl (such as heteroalkyl and heterocycloalkyl), the heteroatom may occupy a position in which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic fragments include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl , tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl and 2-piperazinyl.

The term “halogen” or “halogenide” alone or as part of another substituent means, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom. In addition, the term “haloalkyl” is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halogen (C ₁ -C ₄ ) alkyl" is intended to include, but not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise indicated, a polyunsaturated aromatic substituent, which may be mono-, di- or polysubstituted and may consist of one ring or several rings (preferably 1-3 rings) that are fused together or covalently linked. The term “heteroaryl” refers to an aryl group (or rings) that contain from one to four heteroatoms. In an illustrative embodiment, the heteroatom is selected from B, N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom (s) are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2 -thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2 -quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents of any aryl and heteroaryl ring systems described above are selected from acceptable substituents described below.

For brevity, the term “aryl”, when used in combination with other terms (eg, aryloxy, arylthio, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is intended to include radicals in which the aryl group is attached to an alkyl group (for example, benzyl, phenethyl, pyridylmethyl, etc.), including those alkyl groups in which a carbon atom (for example, methylene group) was substituted, for example, with an oxygen atom, for example, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl and the like.

“Ring or cyclo” means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The so-called ring includes fused ring fragments. The number of atoms in a ring is usually defined as the number of ring members. For example, a “5-7 membered ring” means that 5 to 7 atoms are present in the ring compound. Unless otherwise indicated, the ring optionally includes from one to three heteroatoms. Thus, the term “5-7 membered ring” includes, for example, phenyl, pyridinyl and piperidinyl. The term “5-7 membered heterocycloalkyl ring”, on the other hand, includes pyridinyl and piperidinyl, but not phenyl. The term “ring” further includes a ring system containing at least one ring, where each “ring” is independently defined above.

The term “heteroatom” as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium ( Ge), aluminum (Al), boron (B), etc.

The term “leaving group” means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction (such as a nucleophilic substitution reaction). For example, illustrative leaving groups include triflate, chlorine, bromine, and iodine groups; sulfonic ester groups such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

The term “protecting group” includes, without limitation, an “amino protecting group”, a “hydroxy protecting group” or a “thiol protecting group”. The term “amino protecting group” means a protecting group suitable for preventing side reactions with amine nitrogen. Illustrative amino protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl, trichloroacetyl or trifluoroacetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr) and 1,1-di- (4'-methoxyphenyl) methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); etc. The term “hydroxy protecting group” means a protecting group suitable for preventing adverse reactions to the hydroxy group. Illustrative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); etc.

Examples of halogenated include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl. “Alkoxy” means an alkyl group as defined above with the indicated number of carbon atoms attached via an oxygen bridge. C _1-6 alkoxy is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and sec-pentoxy. “Cycloalkyl” is intended to include saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7-Cycloalkyl is intended to include C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and with one or more unsaturated carbon-carbon bonds, which can be at any stable point along the chain, such as ethenyl and propenyl. The term "halogen" or "halide" refers to fluorine, chlorine, bromine and iodine.

The term “heterocycle” or “heterocycle” is intended to mean a stable monocyclic or bicyclic or bicyclic heterocyclic ring, which may be saturated, partially unsaturated or unsaturated (aromatic) and include carbon atoms and 1, 2, 3 or 4 heteroatoms in the ring, independently selected from the group including N, O and S, wherein any of the above heterocyclic rings may be fused to a benzene ring to form a bicyclic group. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R represents H or other substituents already defined herein). A heterocyclic ring can be attached to its side group at any heteroatom or carbon atom, which provides a stable structure. The heterocyclic rings described herein can be substituted at the carbon atom or at the nitrogen atom, if the resulting compound is stable. The nitrogen atom in the heterocycle may optionally be quaternized. In a preferred embodiment, if the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean a stable 5-, 6- or 7-membered monocyclic or bicyclic or 7-, 8-, A 9- or 10-membered bicyclic heterocyclic aromatic ring that includes carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. The nitrogen atom may or may not be substituted n (i.e., N or NR, where R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). It should be noted that the total number of S and O atoms in an aromatic heterocycle does not exceed 1. Rings with internal bridges are also included in the definition of a heterocycle. A ring with an internal bridge arises if one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred rings with internal bridges include, without limitation, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It should be noted that the bridge always turns a monocyclic ring into a tricyclic ring. In a ring with an internal bridge, substituents in the ring may also be present on the bridge.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benztiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl-2-azinolinyl-2-azinolinyl-2-azinolinyl-2-azolinyl-2-azinolinyl-2-azolinyl-2-azolinyl-2-azolinyl-azinol-2-azolinyl-azinol-2-azolinyl-azinol-2-azolinyl-azinol-2-azinolinyl , 6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolisinyl, indolyl, 3n-indolyl sludge, isobenzofuranyl, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxazyl, 1,2,3-oxazyl, 1,2,3-oxazolaz oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthroinyl, phenazinyl, phenothiazinyl, phenoxatin, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, piperidinyl , pyrazinyl, pyrazolidinyl, pyrazole Inyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolynyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl-tetrahydrodinolinyl-tetrahydrodinolinyl-tetra-di-ynro-yl-inol-tetra-di-ynol-in-tetrahydrodinol-in-tetrahydrodinolinyl, 1,2,5-thiadiazenyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and cc antenil. Also included are fused rings and spiro compounds.

The compounds of the present invention can be obtained by several synthetic methods known to a person skilled in the art, including the specific embodiments described below, the embodiments formed by combining them with other chemical synthesis methods known in the art and equivalents well known specialists in this field. Preferred embodiments include, without limitation, examples of the present invention.

All solvents used herein are commercially available and are used without further purification. The reactions are usually carried out in anhydrous solvents under an inert atmosphere of nitrogen. Proton NMR data were recorded on a Bruker Avance III 400 spectrometer (400 MHz) and chemical shifts are expressed as δ (ppm) with a shift towards a weaker field from tetramethylsilane. Mass spectra were determined using an Agilent 1200 Plus 6110 Series Instrument (& 1956A). LC / MS or Shimadzu MS includes DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) that operates in positive or negative mode.

The following abbreviations apply in this document: aq. means water; HATU is O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; EDC means N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, m-CPBA means 3-chloroperoxybenzoic acid; eq. means equivalent; CDI means carbonyl diimidazole; DCM means dichloromethane; PE means petroleum ether; DIAD means diisopropyl azodicarboxylate; DMF means N, N-dimethylformamide; DMSO means dimethyl sulfoxide; EtOAc means ethyl acetate; EtOH means ethanol; MeOH means methanol; CBz means benzyloxycarbonyl, an amino protecting group; BOC means tert-butylcarbonyl, an amino protecting group; HOAc means acetic acid; NaCNBH ₃ means sodium cyanoborohydride; rt means room temperature; O / N means overnight; THF means tetrahydrofuran; Boc ₂ O means di-tert-butyl dicarbonate; TFA means trifluoroacetic acid; DIPEA means diisopropylethylamine; SOCl ₂ means sulfur dioxide-dichloride; CS ₂ means carbon disulfide; TsOH means 4-methylbenzenesulfonic acid; NFSI is N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS means N-chlorosuccinimide; n-Bu ₄ NF means tetrabutylammonium fluoride; i-PrOH means 2-propanol and so pl. mean melting point.

Compounds were named either manually, or using ChemDraw®, or using vendor catalog names if they were commercially available.

HPLC analyzes were performed using a Shimadzu LC20AB system with a Shimadzu SIL-20A automatic sampling probe and a Shimadzu DAD detector: SPD-M20A. The column used was Xtimate C18, 3 μm, 2.1 × 300 mm. Method 0-60 AB_6 min included: applying a linear gradient, the beginning of the elution at 100% A (A: 0.0675% TFA in water) and the end of the elution at 60% B (B: 0.0625% TFA in MeCN) in total for 4.2 min and then elution at 60% B for 1.0 min. Then the column was re-equilibrated for 0.8 min to 100: 0 with a total run time of 6 min. The 10-80AB_6 min method included: applying a linear gradient, start of elution at 90% A (A: 0.0675% TFA in water) and end of elution at 80% B (B: 0.0625% TFA in MeCN) for a total of 4.2 minutes and then elution at 80% In for 1.0 min. Then the column was re-balanced for 0.8 min to 90:10 with a total run time of 6 min. The column temperature was 50 ° C. at a flow rate of 0.8 ml / min. A diode array detector scanned from 200 to 400 nm.

Thin layer chromatography (TLC) was performed on silica gel GF254 from Sanpont-group and UV was usually used to visualize the spots. In some cases, additional visualization methods have also been used. In these cases, a plate was developed for TLC with iodine (obtained by adding about 1 g of I ₂ to 10 g of silica gel and thoroughly mixing), vanillin (obtained by dissolving approximately 1 g of vanillin in 100 ml of 10% H ₂ SO ₄ ), ninhydrin (available commercially from Aldrich) or Magic Stain (obtained by thoroughly mixing (NH ₄ ) ₆ Mo ₇ O ₂₄ ⋅ 4H ₂ O, 5 g (NH ₄ ) ₂ Ce (IV) (NO ₃ ) ₆ , 450 ml of H ₂ O and 50 ml of concentrated H ₂ SO ₄ ) to visualize the compound. Flash chromatography was performed using 40-63 μm (230-400 mesh) Silica gel from Silicycle, following procedures similar to those disclosed in Still, W.C .; Kahn, M .; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923-2925. Typical solvents used for flash chromatography or thin layer chromatography were mixtures such as dichloromethane / methanol, ethyl acetate / methanol and hexanes / ethyl acetate.

Preparative chromatography was performed using a Gilson-281 Prep LC 322 system using a Gilson UV / VIS-156 detector. The column used was Agella Venusil ASB Prep C18, 5 μm, 150 × 21.2 mm or Phenomenex Gemini C18, 5 μm, 150 × 30 mm or Boston Symmetrix C18, 5 μm, 150 x30 mm or Phenomenex Synergi C18, 4 μm, 150 × 30 mm. Narrow gradients with acetonitrile / water, where the water contained 0.05% HCl or 0.25% HCOOH or 0.5% NH ₃ ⋅H ₂ O, was used to elute the compounds at a flow rate of about 25 ml / min and a total run time of 8 -15 minutes

SFC analyzes were performed using an Agilent 1260 Infinity SFC system with an Agilent 1260 automatic sampler and an Agilent DAD: 1260 detector.

The column used was Chiralcel OD-H 250 × 4.6 mm ID, 5 μm or Chiralpak AS-H 250 × 4.6 mm ID, 5 μm or Chiralpak AD-H 250 × 4.6 mm ID, 5 μm. The OD-H_5_40_2.35 ml method included the following: column used: Chiralcel OD-H 250 × 4.6 mm ID, 5 μm, mobile phase: 40% ethanol (0.05% DEA) in CO ₂ , flow rate: 2, 35 ml / min, wavelength: 220 nm. Method AS-H_3_40_2.35 ml included the following: column used: Chiralpak AS-H 250 × 4.6 mm ID, 5 μm, mobile phase: 40% methanol (0.05% DEA) in CO ₂ , flow rate: 2, 35 ml / min, wavelength: 220 nm. The OD-H_3_40_2.35 ml method included the following: column used: Chiralcel OD-H 250 × 4.6 mm ID, 5 μm, mobile phase: 40% methanol (0.05% DEA) in CO ₂ , flow rate: 2, 35 ml / min, wavelength: 220 nm. Method AD-H_2_50_2.35 ml included the following: column used: Chiralpak AD-H 250 × 4.6 mm ID, 5 mm, mobile phase: 50% methanol (0.1% MEA) in CO ₂ , flow rate: 2, 35 ml / min, wavelength: 220 nm.

Preparative SFC analysis was performed using a Waters Thar 80 Pre-SFC system using a Gilson UV detector. The column used was Chiralcel OD-H 250 × 4.6 mm ID, 5 m or Chiralpak AD-H 250 × 4.6 mm ID, 5 m. Narrow gradients with ethanol or methanol in CO ₂ , where ethanol or methanol contained 0, 05% NH ₃ ⋅H ₂ O or 0.05% DEA or 0.1% MEA was used to elute the compound at a flow rate of 40 to 80 ml / min and a total run time of 20-30 min

The PARP-1 inhibitors provided herein can be used to treat a wide range of diseases, including cancer, stroke, cardiac ischemia, inflammation and diabetes. PARP-1 inhibitors can be used as an independent agent or in combination with other chemotherapeutic agents to enhance the effect of these standard chemotherapeutic agents.

The types of cancer that can be treated with PARP-1 inhibitors include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, leukemia, etc.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided for a more detailed description of the present invention. However, the scope of the present invention is not limited to them.

Scheme A

Example 1

6-Fluoro-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 1A

tert-Butyl-4 - ((tosyloxy) methyl) piperidine-1-carboxylate

To a solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (10 g, 46.5 mmol), Et ₃ N (5.64 g, 55.8 mmol) and DMAP (1.13 g, 9 , 3 mmol) in DCM (100 ml) were added TosCl (9.73 g, 51.2 mmol) in portions at 0 ° C under N ₂ . After stirring at 17 ° C for 2 hours, water (100 ml) was added to quench it. The aqueous layer was extracted with DCM (100 ml × 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by column chromatography to give the title compound (17 g, 99% yield) as a white solid. LCMS (ESI) mass / charge: 370 (M + 1).

Example 1B

tert-Butyl 4- (cyanomethyl) piperidine-1-carboxylate

For the mixture of Example 1A (19 g, 55.7 mmol), sodium cyanide (8.19 g, 167 mmol) in dimethyl sulfoxide (100 ml), the reaction was maintained at 100 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with water (200 ml). The aqueous layer was extracted with EtOAc (100 ml × 3). The combined organic layers were washed with water (50 ml) and brine (50 ml), then dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (11 g), which could be used directly in the next step without further purification. LCMS (ESI) mass / charge: 225 (M + 1).

Example 1C

tert-Butyl 4- (1-cyano-2-oxoethyl) piperidine-1-carboxylate

To a mixture of Example 1B (11 g, 49 mmol), tert-BuOK (32.9 g, 294 mmol) in DMF (80 ml) was added dropwise a solution of ethyl formate (21.7 g, 294 mmol) in DMF (50 ml) at -10 ° C in an atmosphere of N ₂ . After completion of the dropwise addition, the mixture was stirred at 17 ° C for 16 hours, and then neutralized with 1H. HCl. The aqueous layer was extracted with EtOAc (100 ml × 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (11 g, 89%), which could be used directly in the next step without further purification. LCMS (ESI) mass / charge: 253 (M + 1).

Example 1D

(2,6-Dibromo-4-fluorophenyl) hydrazine

To a solution of 2,6-dibromo-4-fluoroaniline (5 g, 18.6 mmol) in 35 ml of 20% aq. HCl (35 ml) was added dropwise a solution of NaNO ₂ (1.41 g, 20.45 mmol) in water (40 ml) at -5 ° C with a dropwise addition rate sufficient to maintain the internal temperature below 5 ° C. After 0.5 h, the above solution was added dropwise to a solution of SnCl ₂ (10.49 g, 46 mmol) in a concentrated solution of HCl (40 ml) at -15 ° C. After completion of the dropwise addition, the mixture was heated to 35 ° C and stirred for 12 hours. The mixture was cooled to 0 ° C and adjusted to pH = 9 with concentrated aqueous ammonia. The aqueous layer was extracted with EtOAc (150 ml × 3). The organic layers were washed with water (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by column chromatography to give the title compound (4 g, yield: 76%). ¹ H NMR (400 MHz, CDCl ₃ -d): δ ppm 3.91 (br.s., 1H), 5.37 (br.s. 1H), 7.31 (d, J = 7.37 Hz , 2H).

Example 1E

tert-Butyl-4- (1-cyano-2- (2- (2,6-dibromo-4-fluorophenyl) hydrazono) ethyl) piperidine-1-carboxylate

A mixture of Example 1C (3.5 g, 13.87 mmol) and Example 1D (3.94 g, 13.87 mmol) in EtOH (30 ml) was stirred at 80 ° C. for 0.5 h. After removing the solution under by vacuum, the residue was purified by column chromatography to give the title compound as a white solid (3.8 g, 53%). LCMS (ESI) mass / charge: 519 (M + 1).

Example 1F

tert-Butyl-4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazol-4-yl) piperidine-1-carboxylate

A mixture of Example 1E (3.8 g, 7.33 mmol) and Et ₃ N (1.48 g, 14.67 mmol) in EtOH (30 ml) was stirred at 80 ° C. for 16 hours. The mixture was evaporated in vacuo with obtaining the title compound, which could be used directly in the next step without further purification. (3.8 g, 100%).

Example 1G

tert-Butyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) piperidine-1-carboxylate

A mixture of Example 1F (2.4 g, 4.63 mmol), N ¹ , N ^2- dimethylethane-1,2-diamine (40.83 mg, 0.463 mmol), CuI (88 mg, 0.463 mmol) and K ₃ PO ₄ (983 mg, 4.63 mmol) in DMF (30 ml) was stirred at 60 ° C for 1 h under microwave radiation in an atmosphere of N ₂ . The mixture was cooled to room temperature, and then filtered through a pad of celite, and the filtrate was evaporated in vacuo to give a residue, which was purified by column chromatography to give the title compound as a white solid (0.4 g, 15%).

LCMS (ESI) mass / charge: 437, 439 (M, M + 2).

Example 1H

Methyl-3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxylate

A mixture of example 1G (200 mg, 0.457 mmol), Pd (OAc) ₂ (10.27 mg, 0.0457 mmol), Pd (dppf) Cl ₂ (33.46 mg, 0.0457 mmol), xanthos (53 mg , 0.0914 mmol), DPPP (38 mg, 0.0914 mmol), PPh ₃ (24 mg, 0.0914 mmol) and Et ₃ N (232 mg, 2.29 mmol) in DMF (40 ml) and MeOH (20 ml) was stirred at 120 ° C for 12 h in a CO atmosphere (3 MPa). The mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was evaporated to give a residue, which was purified by column chromatography to give the title compound as a white solid (100 mg, 52%). LCMS (ESI) mass / charge: 417 (M + 1).

Example 1I

tert-Butyl-4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) piperidine-1-carboxylate

For the mixture of Example 1H (100 mg, 0.24 mmol) and NH ₃ -MeOH (30 ml) in DMF (100 ml), the reaction was carried out at 120 ° C. for 16 hours in a closed tube. The mixture was cooled, and then the solution was removed in vacuo, and the residue was purified by column chromatography to give the title compound as a white solid (70 mg, 73%). LCMS (ESI) mass / charge: 402 (M + 1).

Example 1J

6-Fluoro-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixed solution of Example 1I (70 mg, 0.174 mmol) in DCM (3 ml) and TFA (1 ml) was stirred at 15 ° C. for 1 h, and the solution was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (25 mg, 49%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.93-1.96 (m, 2H), 2.37-2.36 (d, 2H), 3.09-3.22 (m, 3H ), 3.31-, 53 (t, 2H), 7.37-7.39 (m, 1H), 7.68-7.74 (m, 2H). LCMS (ESI) mass / charge: 302 (M + 1).

Example 2

3- (1-Ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 1J (750 mg, 2.49 mmol) and acetaldehyde (1.1 g, 24.9 mmol) in MeOH (15 ml) was stirred at 50 ° C. for 0.5 h. After this, NaCNBH ₃ was added. (3.13 g, 49.8 mmol). The resulting mixture was stirred at 50 ° C. for 16 hours. After removal of the solution under vacuum, the residue was purified by column chromatography to give the title compound as a white solid (563.1 g, 69%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.31-1.34 (t, 3H), 1.94-1.97 (m, 2H), 2.27-2.31 (d, 2H) ), 2.82 (t, 2H), 2.97-3.02 (m, 3H), 3.47-3.48 (d, 2H), 7.34-7.37 (m, 1H), 7.67-7.72 (m, 2H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 3

6-Fluoro-3- (1- (2-fluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 1J (112 mg, 0.372 mmol), 1-bromo-2-methoxyethane (71 mg, 0.558 mmol) and potassium carbonate (154 mg, 1.116 mmol) in acetonitrile (20 ml) was stirred at 40 ° C. for 16 hours . The mixture was cooled and filtered, and the filtrate was evaporated in vacuo to give a residue, which was purified by preparative HPLC to give the title compound (4.6 mg, 3.6%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.94-2.15 (m, 2H), 2.17-2.37 (m, 2H), 2.86-3.07 (m, 3H ), 3.27-3.32 (m, 1H), 3.35-3.39 (m, 1H), 3.46-3.61 (m, 2H), 4.71-4.80 (m , 1H), 4.89 (br.s., 1H), 7.28-7.41 (m, 1H), 7.60-7.76 (m, 2H), 8.24-8.69 ( m, 1H). LCMS (ESI) mass / charge: 348 (M + 1).

Example 4

3- (1-cyclopropylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of (1-ethoxycyclopropoxy) trimethylsilane (115 mg, 0.663 mmol), Example 1J (40 mg, 0.133 mmol), HOAc (79 mg, 1.33 mmol) and NaCNBH ₃ (83 mg, 1.33 mmol) in MeOH ( 10 ml) was stirred at 66 ° C for 7 hours. The mixture was cooled and then the solution was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (19.6 mg, 43%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.70-0.79 (m, 4H), 1.84-1.92 (m, 2H), 2.18-2.28 (t, 3H) ), 2.85-2.94 (m, 3H), 3.42-3.45 (d, 2H), 7.33-7.35 (m, 1H), 7.65-7.68 (m , 2H), 8.395 (s, 1H). LCMS (ESI) mass / charge: 342 (M + 1).

Example 5

3- (1- (Cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 1J (12 mg, 0.04 mmol), cyclopropanecarbaldehyde (5.58 mg, 0.08 mmol) and NaCNBH ₃ (50 mg, 0.8 mmol) in MeOH (2 ml) was stirred at 10 ° C for 16 hours. After this, tetraisopropoxy titanium (17 mg, 0.06 mmol) was added to it and stirred continuously for 1 hour. After removing the solution in vacuo, the residue was purified by preparative HPLC to give the title compound (5.2 mg, 37%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.40-0.44 (m, 2H), 0.75-0.79 (m, 1H), 1.12-1.13 (m, 1H ), 2.04 (s, 2H), 2.32-2.36 (d, 2H), 2.9-3.12 (m, 5H), 3.68 (s, 2H), 7.36 -7.39 (m, 1H); 7.68-7.73 (m, 2H); 8.50 (s, 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 6

6-Fluoro-3- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 6A

tert-Butyl-4- (4-benzyl-8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) piperidine-1-carboxylate

A mixture of Example 1I (100 mg, 0.25 mmol), (bromomethyl) benzene (127 mg, 0.748 mmol) and potassium carbonate (103 mg, 0.748 mmol) in acetonitrile (4 ml) was stirred at 60 ° C. for 4 hours. The mixture was cooled and filtered, and the filtrate was evaporated in vacuo to give a residue, which was purified by silica gel chromatography to give the title compound (112.6 mg, 91.8%). LCMS (ESI) mass / charge: 492 (M + 1).

Example 6B

4-Benzyl-6-fluoro-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of a solution of Example 6A (112.6 mg, 0.229 mmol) in DCM (9 ml) of TFA (3 ml) was stirred at 12 ° C. for 2 hours. After removing the solution in vacuo, the title compound (115 mg, 100%) was obtained as a yellow solid, which could be used directly in the next step without further purification. LCMS (ESI) mass / charge: 392 (M + 1).

Example 6C

4-benzyl-6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 6B (115 mg, 0.229 mmol), 2,2-dimethyloxyran (50 mg, 0.690 mmol) and Et ₃ N (116 mg, 1.15 mmol) in ethanol (5 ml) was heated at 120 ° C. under microwave irradiation. within 1 hour. The mixture was cooled and the solution was removed in vacuo, and then the residue was purified by silica gel chromatography to give the title compound. LCMS (ESI) mass / charge: 464 (M + 1).

Example 6D

6-Fluoro-3- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 6C (32 mg, 0.069 mmol) and Pd / C (25 mg) in methanol (30 ml) was hydrogenated at 50 ° C for 4 hours in an atmosphere of H ₂ (1 ATM). The mixture was cooled and filtered, and the filtrate was evaporated in vacuo. After that, the residue was purified by preparative HPLC to give the title compound (8.2 mg, 32.2%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.38 (s, 6H), 2.10-2.30 (m, 4H), 3.12 (s, 5H), 3.57-3, 73 (m, 2H), 7.29-7.39 (m, 1H), 7.61-7.69 (m, 1H), 7.69-7.75 (m, 1H), 8.54 ( br.s., 1H). LCMS (ESI) mass / charge: 374 (M + 1).

Example 7

6-Fluoro-3- (1- (2-fluoro-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 7A

4-Benzyl-6-fluoro-3- (1- (2-fluoro-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

To a mixture of Example 6C (32 mg, 0.069 mmol) in DCM (10 ml) was added dropwise a solution of DAST (33 mg, 0.207 mmol) in DCM (2 ml) at 0 ° C. under N ₂ . After completion of the dropwise addition, the mixture was stirred at 17 ° C for 16 hours, and then quenched with saturated sodium bicarbonate solution (10 ml). The aqueous layer was extracted with EtOAc (10 ml × 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography to give the title compound (27 mg, 84.4%). LCMS (ESI) mass / charge: 466 (M + 1).

Example 7B

6-Fluoro-3- (1- (2-fluoro-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 7A (27 mg, 0.058 mmol) and Pd / C (30 mg) in methanol (20 ml) was hydrogenated at 45 ° C for 16 hours in an atmosphere of H ₂ (1 atm). The mixture was cooled and filtered, and the filtrate was evaporated. The residue was purified by preparative HPLC to give the title compound (2.1 mg, 10%). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.42 (s, 3H), 1.48 (s, 3H), 1.90-2.03 (m, 2H), 2.04-2, 16 (m, 2H), 2.51-2.67 (m, 2H), 2.72-2.90 (m, 3H), 3.23-3.31 (m, 2H), 7.32- 7.41 (m, 1H); 7.63-7.75 (m, 2H); 8.27-8.59 (m, 1H). LCMS (ESI) mass / charge: 376 (M + 1)

Example 8

3- (1- (Cyclopropylcarbonyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 1J (52 mg, 0.125 mmol), cyclopropanecarboxylic acid (13 mg, 0.150 mmol), Et ₃ N (50.5 mg, 0.5 mmol) and HATU (47.5 mg, 0.125 mmol) in acetonitrile (5 ml) was stirred at 50 ° C for 3 hours. After cooling the mixture and removing the solution under vacuum, the residue was purified by preparative HPLC to give the title compound (12.7 mg, 27.3%). LCMS: 370 [M + 1]. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 0.72 (d, J = 7.53 Hz, 4H), 1.42-1.69 (m, 2H), 1.88-2.07 ( m, 3H), 2.65-2.77 (m, 1H), 2.86-2.98 (m, 1H), 3.14-3.29 (m, 1H), 4.26-4, 50 (m, 2H), 7.43-7.50 (m, 1H), 7.51-7.59 (m, 1H), 7.76 (s, 1H). LCMS (ESI) mass / charge: 370 (M + 1).

Example 9

6-Fluoro-3- (1-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.98-2.01 (d, 2H), 2.29-2.31 (d, 2H), 2.83 (s, 1H), 3.01-3.04 (d, 2H), 3.48 (d, 2H), 7.36-7.39 (m, 1H), 7.68-7, 73 (m, 2H), 8.49 (s, 1H), LCMS (ESI) mass / charge: 316 (M + 1).

Example 10

6-Fluoro-3- (1-isopropylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.38-1.40 (d, 6H), 2.02-2.05 (d, 2H), 2.36-2.40 (d, 2H), 3.06 (m, 1H), 3.19-3.22 (t, 2H), 3.51-3.55 (m, 3H), 7, 35-7.38 (m, 1H), 7.66-7.72 (m, 2H), 8.51 (s, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 11

6-Fluoro-3- (1- (oxetan-3-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 2. ¹ H NMR (400 MHz, DMSO-d ₆₎ ppm 1,66-1,79 (m, 2H), 1,82-1,99 (m, 4H), 2.58-2.69 (m, 1H), 2.70-2.81 (m, 2H), 3.36-3.45 (m, 1H), 4.45 (s, 2H), 4, 51-4.58 (m, 2H), 7.36-7.44 (m, 1H), 7.45-7.53 (m, 1H), 7.65-7.75 (m, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 12

6-Fluoro-3- (1-propylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (400 MHz, methanol-d ₄ ) ppm 1.02-1.06 (t, 3H), 1.76-1.82 (m, 2H) 2.00-2.03 (d, 2H), 2.31-2.34 (d, 2H), 3.01-3.05 (m, 5H), 3.57-3.58 (d , 2H), 7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H), 8.5l (s, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 13

3- (1- (2-aminoethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.80-1.98 (m, 2H), 2.06-2.17 (m, 2H), 2.30-2.46 (m, 2H), 2.68-2.85 (m, 3H), 3.05-3.19 (m, 4H), 7.30-7.38 (m, 1H ), 7.69 (br.s., 2H), 8.28-8.67 (m, 1H). LCMS (ESI) mass / charge: 345 (M + 1).

Example 14

3- (1- (2- (Dimethylamino) ethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 2. ¹ H NMR (400 MHz, methanol-d ₄₎ ppm 1,83-1,98 (m, 2H), 2,05-2,18 (m, 2H), 2.36-2.48 (m, 2H), 2.68 (s, 6H), 2.80 (t, J = 6.46 Hz, 3H), 2.97-3.07 (m, 2H) 3.11-3.25 (m, 2H); 7.25-7.40 (m, 1H); 7.57-7.75 (m, 2H). LCMS (ESI) mass / charge: 373 (M + 1).

Example 15

6-Fluoro-3- (1- (2-methoxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 2.00-2.18 (m, 2H), 2.22-2.38 (m, 2H), 2.94-3.08 (m, 1H), 3.08-3.22 (m, 2H), 3.33-3.38 (m, 2H), 3.44 (s, 3H), 3, 56-3.70 (m, 2H), 3.71-3.82 (m, 2H), 7.19-7.38 (m, 1H), 7.53-7.64 (m, 1H), 7.68 (s, 1H); 8.42-8.66 (m, 1H). LCMS (ESI) mass / charge: 360 (M + 1).

Example 16

6-Fluoro-3- (1- (2-hydroxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 2.04-2.20 (m, 2H), 2.25-2.37 (m, 2H), 2.98-3.10 (m, 1H), 3.12-3.24 (m, 2H), 3.25-3.31 (m, 2H), 3.62-3.75 (m, 2H) ), 3.89-3.99 (m, 2H), 7.25-7.38 (m, 1H), 7.57-7.66 (m, 1H), 7.69 (s, 1H), 8.50-8.62 (m, 1H). LCMS (ESI) mass / charge: 346 (M + 1).

Example 17

3- (1-Ethylpiperidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1 and 2, replacing tert-butyl-3- (hydroxymethyl) piperidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400 MHz) δ: 1.38 (t, 3H), 1.85-2.00 (m, 2H), 2.13-2.26 (m, 2H), 2.94 -3.03 (m, 2H), 3.21-3.24 (m, 3H), 3.59-3.73 (m, 2H), 7.37-7.39 (dd, 1H), 7 66-7.69 (dd, 1H); 7.76 (s, 1H); 8.52 (bs, 1H). LCMS (ESI) mass / charge: 331 (M + 1).

Example 18

3- (1-Ethylazepan-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 18A

1-tert-Butyl-4-ethyl-5-oxoazepan-1,4-dicarboxylate

Ethyl 2-diazo was added dropwise to a solution of tert-butyl 4-oxopiperidin-1-carboxylate (50 g, 251 mmol) and BF ₃ -Et ₂ O (49.86 g, 351 mmol) in THF (500 ml). (40.09 g, 351 mmol) at -40 ° C in an atmosphere of N ₂ . After completion of the dropwise addition, the mixture was stirred at -40 ° C for 2 hours, then heated to 15 ° C and stirred for 16 hours. After completion of the reaction, the mixture was quenched with an aqueous solution of K ₂ CO ₃ (500 ml). The aqueous layer was extracted with EtOAc (500 ml × 2). The combined organic layers were washed with water and brine, then dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography to give the title compound (45 g, yield: 63%). LCMS (ESI) mass / charge: 286 (M + 1).

Example 18B

1-tert-Butyl 4-ethyl-5-hydroxyazepan-1,4-dicarboxylate

To a solution of Example 18A (45 g, 157.7 mmol) in MeOH (420 ml) NaBH ₄ (7.16 g, 189 mmol) was added in portions at 0 ° C. After stirring at 0 ° C for 1 h, the resulting mixture was quenched with water (400 ml), and the aqueous phase was extracted with EtOAc (400 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography to give the title compound (22.3 g, yield: 49%). LCMS (ESI) mass / charge: 288 (M + 1).

Example 18C

1-tert-Butyl-4-ethyl-2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

To a solution of Example 18B (21 g, 73 mmol), DBU (22 g, 146 mmol) in toluene (200 ml) was added dropwise MsCl (14.56 g, 128 mmol). After completion of the dropwise addition, the mixture was stirred at 110 ° C for 2 h and cooled to room temperature, and then water (200 ml) was added to quench it. The aqueous layer was extracted with EtOAc (200 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography to give the title compound (13 g, yield: 66%). LCMS (ESI) mass / charge: 270 (M + 1).

Example 18D

1-tert-butyl-4-methyl-azepan-1,4-dicarboxylate

A mixture of Example 18C (13 g, 48.27 mmol) and Pd / C (1 g) in MeOH (130 ml) was hydrogenated at 15 ° C for 16 h in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was evaporated to give the title compound, which could be used directly in the next step without further purification (10.7 g, yield: 82%). LCMS (ESI) mass / charge: 258 (M + 1).

Example 18E

tert-Butyl 4- (hydroxymethyl) azepan-1-carboxylate

To a solution of Example 18D (10.7 g, 39 mmol) in THF (200 ml) was added LiAlH ₄ (1.48 g, 39 mmol) in portions at 0 ° C. After stirring at 0 ° C for 30 min, the resulting mixture was quenched with water (10 ml), 15% aq. NaOH (10 ml), water (30 ml). The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography to give the title compound (7 g, yield: 77%). LCMS (ESI) mass / charge: 230 (M + 1).

Example 18F

3- (1-Ethylazepan-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1 and 2, replacing tert-butyl 4- (hydroxymethyl) azepan-1-carboxylate with tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400 MHz) δ: 1,38-1,42 (t, 3H), 1,93-1,96 (m, 2H), 1,99-2,12 (m, 2H) 2.32-2.34 (m, 2H); 3.15-3.30 (m, 1H); 3.32-3.33 (m, 2H); 3.33-3.53 (m, 4H), 7.38-7.40 (dd, 1H), 7.69-7.73 (dd, 1H), 7.74 (s, 1H), 8.50 (bs, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 19

6-Fluoro-3- (1-methylazepan-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 18. ¹ H-NMR (MeOD, 400 MHz) δ: 1,95-2,10 (m, 3H), 2,26-2,35 (m, 3H), 2 96 (s, 1H), 3.14-3.17 (m, 1H), 3.36-3.49 (m, 4H), 7.38-7.40 (dd, 1H), 7.69 -7.72 (dd, 1H); 7.74 (s, 1H); 8.47 (bs, 1H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 20

6-Fluoro-3- (1-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1 and 2, replacing tert-butyl-3- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400 MHz) δ: 2.29-2.35 (m, 1H), 2.59-2.62 (m, 1H), 2.99 (s, 3H), 3.32 -3.36 (m, 1H), 3.53-3.55 (m, 2H), 3.76-3.81 (m, 2H), 7.40-7.42 (dd, 1H), 7 70-7.73 (dd, 1H); 7.80 (s, 1H); 8.50 (bs, 1H). LCMS (ESI) mass / charge: 302 (M + 1).

Example 21

3- (1-Ethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in Example 20, replacing tert-butyl 3- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400 MHz) δ: 2.29-2.35 (m, 1H), 2.59-2.62 (m, 1H), 2.99 (s, 3H), 3.32 -3.36 (m, 1H), 3.53-3.55 (m, 2H), 3.76-3.81 (m, 2H), 7.40-7.42 (dd, 1H), 7 70-7.73 (dd, 1H); 7.80 (s, 1H); 8.50 (bs, 1H). LCMS (ESI) mass / charge: 316 (M + 1).

Example 22

6-Fluoro-3- (1-isopropylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in Example 20, replacing tert-butyl 3- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400 MHz) δ: 1.42-1.44 (d, 6H), 2.25-2.31 (m, 1H), 2.57-2.60 (m, 1H) 3.32-3.33 (m, 1H), 3.44-3.55 (m, 3H), 3.68-3.71 (m, 1H), 7.41-7.43 (dd, 1H), 7.71-7.74 (dd, 1H), 7.82 (s, 1H), 8.55 (bs, 1H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 23

6-Fluoro-3- (pyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 1, replacing tert-butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 2.17-2.31 (m, 1H), 2.33-2.51 (m, 2H), 2.52-2.67 (m , 1H), 3.48 (t, J = 7.28 Hz, 2H), 7.40 (dd, J = 8.03, 2.26 Hz, 1H), 7.65 (dd, J = 10, 79, 2.26 Hz, 1H), 7.94 (s, 1H), 8.55 (br.s., 1H). LCMS (ESI) mass / charge: 288 (M + 1).

Example 24

6-Fluoro-3- (1-propylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 2, replacing tert-butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.93 (t, J = 7.34 Hz, 3H), 1.54-1.79 (m, 2H), 2.23 (d, J = 5.02 Hz, 2H), 2.37-2.53 (m, 2H), 2.76 (br.s., 1H), 3.05 (br.s., 2H), 3.65 (br.s., 1H), 4.31 (br.s., 1H), 7.44 (dd, J = 8.09, 2.32 Hz, 1H), 7.73 (dd, J = 10 92, 2.38 Hz, 1H), 7.94 (s, 1H), 8.54 (br.s., 1H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 25

6-Fluoro-3- (1-methylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 2, replacing tert-butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 2.25-2.41 (m, 2H), 2.47-2.67 (m, 2H), 2.82 (s, 3H), 3.23-3.30 (m, 1H), 3.66-3.79 (m, 1H), 4.50-4.58 (m, 1H), 7.43 (dd, J = 8.16 , 2.51 Hz, 1H), 7.64 (dd, J = 10.73, 2.57 Hz, 1H), 7.95-8.02 (m, 1H), 8.52 (br.s. , 1H). LCMS (ESI) mass / charge: 302 (M + 1).

Example 26

3- (1-Ethylpyrrolidin-2-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 2; replacing tert-butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) piperidine-1-carboxylate. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.30 (t, J = 7.28 Hz, 3H), 2.26-2.37 (m, 2H), 2.46-2, 61 (m, 2H), 2.98-3.09 (m, 1H), 3.25 (d, J-10.29 Hz, 2H), 3.68-3.80 (m, 1H), 4 55 (t, J = 8.78 Hz, 1H), 7.42 (dd, J = 8.16, 2.26 Hz, 1H), 7.64 (dd, J = 10.73, 2.32 Hz, 1H), 7.97 (s, 1H), 8.54 (br.s., 1H). LCMS (ESI) mass / charge: 316 (M + 1).

Example 27

3- (1-Ethylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 1, replacing (2,6-dibromophenyl) hydrazine with (2,6-dibromo-4-fluorophenyl) hydrazine. ¹ H-NMR (400 MHz, methanol-d ₄ ) ppm 1.16-1.20 (t, 3H), 1.84-1.87 (m, 2H), 2.07-2.11 (d, 2H), 2.16-2.19 (d, 2H), 2.51-2.56 (q, 2H), 2.70-2.75 (m, 1H), 3.11-3.13 ( d, 2H), 7.40-7.44 (t, 1H), 7.61-7.63 (m, 1H), 7.70 (s, 1H), 7.99-8.02 (m, 1H). LCMS (ESI) mass / charge: 312 (M + l).

Example 28

6-Fluoro-3- (3-methyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 28A

Ethyl 1-benzyl-2,5-dihydro-1H-pyrrole-3-carboxylate

To a solution of N-benzyl-1-methoxy-N - ((trimethylsilyl) methyl) methanamine (4.5 g, 61 mmol) and ethyl propiolate (5.0 g, 51 mmol) in DCM (150 ml) was added dropwise Et ₃ N (0.4 ml, 5.2 mmol) at 0 ° C. After completion of the dropwise addition, the reaction mixture was stirred at 0 ° C for 1 hour, and heated to 20 ° C, and stirred for 24 h and then quenched with saturated NaHCO ₃ (100 mL). The aqueous phase was extracted with DCM (250 ml × 2). The combined organic layers were washed with brine (150 ml × 2) and dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (10 g, yield: 80%) as a yellow oil. LCMS (ESI) mass / charge: 232 (M + 1).

Example 28B

Ethyl 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carboxylate

To a mixture of (CH ₃ ) ₃ SOI (21.5 g, 97.7 mmol) in DMSO (150 ml) was added 60% NaH (3.5 g, 87.5 mmol) in portions at 0 ° C - 5 ° C atmosphere N ₂ . After complete addition, the mixture was stirred at 19 ° C for 2 hours, and then the solution of Example 28A (9 g, 38.9 mmol) was added portionwise to it at 0 ° C-5 ° C. The mixed reaction solution was stirred at 19 ° C. for 15 hours, and then quenched with saturated NaHCO ₃ (300 ml). The aqueous phase was extracted with DCM (500 ml × 2). The combined organic layers were washed with brine (200 ml × 2) and dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (5.4 g, yield: 32%) as a yellow oil. LCMS (ESI) mass / charge: 246 (M + 1).

Example 28C

3-tert-Butyl-1-ethyl-3-azabicyclo [3.1.0] hexane-1,3-dicarboxylate

A mixture of Example 28B (5.4 g, 22 mmol), BOC ₂ O (10 g, 46 mmol) and 10% Pd / C (600 mg) in MeOH (100 ml) were hydrogenated at 19 ° C. for 15 hours in atmosphere H ₂ (1 atm). The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (5.3 g, yield: 94%) as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃₎ δ ppm 0,83 (t, J = 4,96 Hz, 1H), 1,25 (t, J = 7,15 Hz, 3H), 1,39-1 48 (m, 9 N), 1.56 (dd, J = 8.34, 4.58 Hz, 1H), 1.79 (s, 1H), 1.94-2.10 (m, 1H) 3.41 (dd, J = 10.73, 3.45 Hz, 1H), 3.50-3.82 (m, 3H), 4.07-4.19 (m, 2H), 4.25 (d, J-7.15 Hz, 1H), 5.05 (s, 1H), 6.61 (t, J = l, 88 Hz, 1H), 7.14 (s, 1H), 7.28 -7.38 (m, 1H).

Example 28D

tert-Butyl-1- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

A mixture of example 28C (5.3 g, 20.7 mmol) and 1H. LiOH (50 ml, 50 mmol) in THF (25 ml) and MeOH (50 ml) were stirred at 60 ° C for 2 hours. The mixture was cooled to room temperature and then extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (50 ml × 2), brine (50 ml × 2), dried over Na ₂ SO ₄ and evaporated to give a residue. The residue was dissolved in THF (100 ml) and 10 M BH ₃ -DMS (10 ml, 100 mmol) was added dropwise thereto at 0 ° C. under N ₂ . After completion of the dropwise addition, the mixture was stirred at 19 ° C for 15 hours, and after completion of the reaction, MeOH (100 ml) was quenched. The solution was evaporated in vacuo. The residue was purified by column chromatography to give the title compound (3.5 g, yield: 89%) as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.51 (br.s., 1H, 0.78 (dd, J = 8.09, 5.08 Hz, 1H), 1.37-1, 47 (m, 10H), 3.42 (d, J = 10.29 Hz, 2H, 3.48-3.78 (m, 4H).

Example 28E

tert-Butyl-1- (chloromethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

To a mixture of Example 28D (3.5 g, 16.43 mmol), DMAP (200 mg, 1.6 mmol) and Et ₃ N (5 ml, 36.14 mmol) in DCM (100 ml) were added TosCl (3 7 g, 19.47 mmol) at 0 ° C. After stirring at 24 ° C for 15 hours, the mixture was quenched with water (100 ml). The aqueous layer was extracted with DCM (250 ml × 2).

The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (2.6 g, yield: 68%) as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.68 (t, J = 4.64 Hz, 1H), 0.90 (dd, J = 8.16, 5.27 Hz, 1H), 1 39-1.55 (m, 10H); 3.36-3.46 (m, 2H); 3.48-3.77 (m, 4H).

Example 28F

tert-Butyl-1- (cyanomethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

A mixture of Example 28E (2.6 g, 11 mmol), NaCN (1.57 g, 32 mmol) and KI (1.87 g, 11 mmol) in DMSO (40 ml) was stirred at 100-120 ° C for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc (200 ml) and an aqueous solution of Na ₂ CO ₃ (120 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered and evaporated. The residue was purified by column chromatography to give the title compound (2.4 g, yield: 96%) as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm 0.47-0.72 (m, 1H), 0.81-0.96 (m, 1H), 1.34-1.55 (m, 10H ), 2.53-2.80 (m, 2H), 3.30 (d, J = 10.54 Hz, 1H), 3.38-3.84 (m, 1H). LCMS (ESI) mass / charge: 167 (M-55).

Example 28G

tert-Butyl-1- (1-cyano-2- (dimethylamino) vinyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

A mixture of 1-tert-butoxy-N, N, N ′, N′-tetramethylmethanediamine (3.8 g, 21.8 mmol) and Example 28F (2.4 g, 10.8 mmol) in DMF (20 ml) was stirred at 70 ° C for approximately 10 hours. After cooling to room temperature, the solvent was evaporated from the resulting mixture in vacuo to give the title compound, which could be used directly in the next step without further purification.

Example 28H

tert-Butyl-1- (1-cyano-2-hydroxyvinyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

A solution of Example 28G (3.0 g, crude, 10.8 mmol) in a mixture of THF / HOAc / water (1/1/1) (45 ml) was stirred at 24 ° C. for 5 hours. After removal of the solution in vacuo, the residue was separated. between saturated NaHCO ₃ (100 ml) and EtOAc (100 ml). The aqueous phase was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (100 ml × 2), brine (100 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (1.4 g, yield: 52%) as a yellow oil. LCMS (ESI) mass / charge: 195 (M-55).

Example 28I

3- (3-Azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1E-1J.

Example 28J

6-Fluoro-3- (3-methyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.32 (d, J = 6.40 Hz, 2H), 2.05 (td, J = 6.37, 3.95 Hz, 1H), 2.93 (s, 3H), 3.47 (d, J = 11.04 Hz, 1H), 3.59 (dd, J = 11.11, 3 , 83 Hz, 1H), 3.67-3.76 (m, 1H), 3.85 (d, J = 11.04 Hz, 1H), 7.32 (dd, J = 8.16, 2, 51 Hz, 1H), 7.58 (dd, J = 10.79, 2.51 Hz, 1H), 7.77 (s, 1H), 8.52 (s, 1H). LCMS (ESI) mass / charge: 314 (M + 1).

Example 29

3- (3-Ethyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 28. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.27-1.37 (m, 5H), 1.95-2.11 (m, 1H ), 3.22 (q, J = 7.19 Hz, 2H), 3.41 (d, J-10.92 Hz, 1H), 3.48-3.57 (m, 1H), 3.69 (s, 1H), 3.86 (d, J = 10.92 Hz, 1H), 7.33 (dd, J = 8.16, 2.51 Hz, 1H), 7.64 (dd, J = 10.85, 2.57 Hz, 1H), 7.79 (s, 1H), 8.51 (s, 1H). LCMS (ESI) mass / charge: 328 (M + 1).

Example 30

3- (3-Cyclobutyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 28. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) 0.77 (dd, J = 7.91, 4.14 Hz, 1H), 1, 22 (t, J = 4.14 Hz, 1H), 1.51-1.68 (m, 3H), 1.77-1.96 (m, 4H), 2.47 (br.s., 2H ), 2.88 (d, J = 8.78 Hz, 1H), 2.98-3.13 (m, 2H), 7.44 (dd, J = 8.41, 2.51 Hz, 1H) 7.52 (dd, J = 10.98, 2.57 Hz, 1H); 7.71 (s, 1H). LCMS (ESI) mass / charge: 354 (M + 1).

Example 31

3- (3- (Cyclopropylmethyl) -3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 28. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 0.32-0.35 (m, 2H), 0.65-0.68 (m, 2H) 1.06 (m, 1H), 1.16-1.19 (m, 1H), 1.39-1.42 (t, 1H), 1.92-1.94 (m, 1H), 2 84-2.85 (d, 2H), 3.18-3.21 (m, 1H), 3.56-3.59 (d, 2H), 3.73-3.75 (d, 2H) 7.35-7.39 (dd, 1H); 7.68-7.71 (dd, 1H); 7.78 (s, 1H); 8.55 (s, 1H). LCMS (ESI) mass / charge: 354 (M + 1).

Example 32

6-Fluoro-3- (3-isopropyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 28. ¹ H-NMR (400 MHz, methanol-d ₄ ) 1.25-1.43 (m, 8H), 2.00-2.15 (m, 1H), 3.39 (s, 1H), 3.49 (d, J = 11.04 Hz, 1H), 3.62 (d, J = 3.89 Hz, 1H), 3.71 (s, 1H), 3.90 (d, J = 10.92 Hz, 1H), 7.29-7.40 (m, 1H), 7.64 (dd, J = 10.85, 2.57 Hz, 1H), 7 79 (s, 1H); 8.52 (br.s., 1H). LCMS (ESI) mass / charge: 342 (M + 1).

Example 33

3- (3-Azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 33A

Ethyl 5-benzyl-4,6-dioxo-1, Za, 4,5,6,6a-hexahydro-pyrrolo [3,4-c] pyrazole-3-carboxylate

A mixture of 1-benzyl-1H-pyrrole-2,5-dione (5.0 g, 26.7 mmol) and 2-propionyldiazenecarbaldehyde (2.9 ml, 28.0 mmol) in toluene (30 ml) was stirred at 30 ° C for 5 hours. After removing the solution under vacuum, the residue was purified by silica gel chromatography to give the title compound (7.67 g, 95.4% yield). LCMS (ESI) mass / charge: 302 (M + 1).

Example 33B

Ethyl 3-benzyl-2,4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylate

Example 33A (7.67 g, 25.5 mmol) was heated to 190 ° C. for 1 hour. The residue was purified by chromatography to give the title compound (5.353 g, 76.9%) as a white solid. LCMS (ESI) mass / charge: 274 (M + 1).

Example 33C

(3-Benzyl-3-azabicyclo [3.1.0] hexan-6-yl) methanol

To a suspension of LiAlH ₄ (3.055 g, 80.4 mmol) in THF (50 ml) was added dropwise to a solution of Example 33B (5.353 g, 19.6 mmol) in 30 mL of THF at 0 ° C under N _2. After heating under reflux for 16 hours, the reaction mixture was quenched with a saturated aqueous solution of Na ₂ SO ₄ (5 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by chromatography to give the title compound (1.42 g, 35.8%). LCMS (ESI) mass / charge: 204 (M + 1).

Example 33D

tert-Butyl-6- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

A mixture of Example 33C (1.42 g, 7.0 mmol), Boc ₂ O (1.81 g, 8.4 mmol) and 10% Pd / C (200 mg) in methanol (80 ml) was hydrogenated at 25 ° C. for 16 hours in an atmosphere of H ₂ (1 ATM). The mixture was filtered and the filtrate was evaporated to give a residue, which was purified by chromatography to give title compound 4 (1.14 g, 76%). LCMS (ESI) mass / charge: 214 (M + 1).

Example 33E

3- (3-Azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1E-1J. ¹ H NMR (400 MHz, methanol-d ₄₎ ppm 1,86-1,95 (m, 1H) , 2,12-2,22 (m, 2H), 3,49-3,65 (m, 4H ), 7.34-7.42 (m, 1H), 7.64-7.74 (m, 2H), 8.42-8.61 (m, 1H). LCMS (ESI) mass / charge: 300 (M + 1).

Example 34

3- (3-Ethyl-3-azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 28. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.26 (s, 3H), 1.95-2.02 (m, 2H), 2.11- 2.18 (m, 1H), 2.85-2.95 (m, 2H), 2.96-3.08 (m, 2H), 3.42-3.58 (m, 2H), 7, 30-7.38 (m, 1H), 7.60-7.65 (m, 1H), 7.65-7.70 (m, 1H). LCMS (ESI) mass / charge: 328 (M + 1).

Example 35

3- (8-Ethyl-8-azabicyclo [3.2.1] octan-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 35A

tert-Butyl-3-cyano-8-azabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (10 g, 44.389 mmol) in DME (300 ml) and EtOH (6.7 ml) were added tert-BuOK (portions) 20 g, 177.557 mmol) and TOSMIC (17.33 g, 88.778 mmol) at 0 ° C in an atmosphere of N ₂ . After stirring at 60 ° C for 16 hours, the resulting mixture was quenched with water (100 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (6.08 g, yield: 57.96%) as a white solid. LCMS (ESI) mass / charge: 327 (M + 1).

Example 35B

8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] octane-3-carboxylic acid

A solution of example 35A (6.58 g, 27.845 mmol) and KOH (9.36 g, 167.069 mmol) in a mixture of EtOH / H ₂ O (1: 1, 200 ml) was stirred at 80 ° C for 4 hours. Obtained in as a result, the mixture was diluted with water (100 ml) and the aqueous phase was adjusted to pH 3-4 with 2 N. HCl, and then extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound as a white solid, which was used directly in the next step without further purification (6.01 g, yield: 84.53% )

Example 35C

tert-Butyl-3- (hydroxymethyl) -8-azabicyclo [3.2.11 octane-8-carboxylate

To a solution of Example 35B (6 g, 23.529 mmol) in THF (60 ml) was added BH ₃ -DMS at 0 ° C. under N ₂ . After the mixture was stirred at 25 ° C for 16 hours, MeOH (100 ml) was added to quench it. The resulting mixture was evaporated, and the residue was purified by column chromatography to give the title compound (5.2 g, yield: 92.69%). LCMS (ESI) mass / charge: 242 (M + 1).

Example 35D

3- (8-Ethyl-8-azabicyclo [3.2.1] octan-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1E-1J and 2. ¹ H-NMR (MeOD, 400 MHz) δ: 1.42-1.45 (t, 3H), 2.18-2.36 (m, 8 H), 3.16-3.18 (m, 2H), 3.36-3.42 (m, 1H), 4.13 (s, 2H), 7.36-7.37 (dd, 1H) 7.61-7.66 (dd, 1H); 7.68 (s, 1H); 8.62 (bs, 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 36

6-Fluoro-3- (4-hydroxypyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 36A

1- (tert-butyl) 2-methyl-4 - ((tert-butyl diphenylsilyl) oxy) pyrrolidine-1,2-dicarboxylate

To a mixture of 1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.13 mmol), imidazole (1.1 g, 16.26 mmol) in anhydrous DCM (50 ml) TBDPSC1 (2.68 g, 9.76 mmol) was added in portions at 0 ° C. under N ₂ . After stirring at 15 ° C for 4 hours, the reaction mixture was washed with water (10 ml × 2) and dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (3.9 g, yield: 99%) as a colorless oil which could be used directly in the next step without further purification.

Example 36B

1- (tert-butoxycarbonyl) -4 - ((tert-butyldiphenylsilyl) oxy) pyrrolidine-2-carboxylic acid

A mixture of Example 36A (3.9 g, 8.1 mmol) and LiOH (1 g, 24.2 mmol) in a mixed solution of H ₂ O (20 ml), MeOH (5 ml) and THF (20 ml) was stirred at 15 ° C for 16 hours. The mixture was diluted with water (50 ml) and adjusted to pH 4-5 with 1N. HCl, and the aqueous layer was extracted with EtOAc (50 ml × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (3.7 g, yield: 97%), which was used directly in the next step without further purification.

Example 36C

tert-Butyl-4 - ((tert-utyldiphenylsilyl) oxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

To the mixture of Example 36B (3.7 g, 7.89 mmol), Et ₃ N (2.2 g, 15.8 mmol) in THF (100 ml) was added isopropyl chloroformate (1.2 g, 9.5 mmol) at 0 ° C in an atmosphere of N ₂ . After stirring at 15 ° C for 4 hours, the mixture was cooled to 0 ° C and NaBH ₄ (1.2 g, 31.56 mmol) was added to it. The reaction mixture was stirred at 15 ° C for 64 hours. After removing the solution in vacuo, the residue was partitioned between water (50 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (50 ml × 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (3.5 g, yield: 100%). LCMS (ESI) mass / charge: 456 (M + 1).

Example 36D

tert-Butyl-4 - ((tert-butyl diphenylsilyl) oxy) -2- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) pyrrolidin- 1-carboxylate

This example was obtained as described in examples 1E-1J. LCMS (ESI) mass / charge: 642 (M + 1).

Example 36E

6-Fluoro-3- (4-hydroxypyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 36D (50 mg, 0.078 mmol) in HBr / HOAc (0.5 ml) was stirred at 15 ° C. for 6 hours. The resulting mixture was evaporated, and the residue was purified by preparative HPLC to give the title compound (10 mg, yield: 43%). ¹ H NMR (400 MHz, DMSO-d ₆ ) = 8.36 (br.s., 1H), 8.06-7.86 (m, 1H), 7.53 (d, J = 9.9 Hz , 2H), 4.91 (dd, J = 6, l, 11.5 Hz, 1H), 4.56 (br.s., 1H), 3.45 (d, J = 8.8 Hz, 1H ), 3.06 (d, J = 12.7 Hz, 1H), 2.48-2.41 (m, 1H), 2.21 (dd, J = 5.8, 13.0 Hz, 1H) . LCMS (ESI) mass / charge: 304 (M + 1).

Example 37

3-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 37A

5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazole-4-carbonitrile

A mixture of Example 1D (4 g, 14 mmol) and 2- (ethoxymethylene) malononitrile (2.24 g, 18.31 mmol) in EtOH (30 ml) was stirred at 80 ° C for 1.5 hours. The mixture was evaporated in vacuo. to obtain the title compound (2.8 g, 56%), which could be used directly in the next step without further purification.

Example 37B

8-Bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carbonitrile

A mixture of example 37A (2.8 g, 7.78 mmol), N ¹ , N ^2- dimethylethane-1,2-diamine (68 mg, 0.777 mmol), CuI (148 mg, 0.777 mmol) and K ₃ PO ₄ ( 1.65 g, 7.78 mmol) in DMF (30 ml) was stirred at 60 ° C for 24 hours in an atmosphere of N ₂ . The mixture was cooled to room temperature and filtered, and the filtrate was evaporated to give a residue, which was washed with MeOH and water, and then dried under vacuum to give the title compound (1.7 g, 78%), which was used directly in the next step without additional cleaning up.

Example 37C

Methyl 3-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxylate

The solution of example 37B (1 g, 3.58 mmol), Pd (OAc) ₂ (161 mg, 0.72 mmol), Pd (dppf) Cl ₂ (526 mg, 0.72 mmol), xanthos (420 mg, 0 , 72 mmol), DPPP (296 mg, 0.72 mmol), PPh ₃ (188 mg, 0.72 mmol) and Et ₃ N (1.8 g, 18 mmol) in DMF (30 ml) and MeOH (10 ml) was stirred at 120 ° C for 12 h in a CO atmosphere (3 MPa). After cooling to room temperature, the mixture was filtered, and the filtrate was evaporated to give a residue, which was washed with DCM and dried. The resulting title compound (0.5 g, 54%) was used directly in the next step without further purification.

Example 37D

3-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 37C (20 mg, 0.077 mmol) and NH ₄ OH (5 ml) in DMF (1 ml) and MeOH (1 ml) was stirred at 120 ° C. for 4 hours. After removing the solution in vacuo, the resulting residue was purified by preparative HPLC to give the title compound (2.99 mg, 16%). ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ ppm 7.52 (dd, J = 7.91 Hz, 1H), 7.80 (dd, J = 10.67 Hz, 1H), 8.19 (s, 1H). LCMS (ESI) mass / charge: 244 (M + 1).

Example 38

3-cyano-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 37. ¹ H NMR (400 MHz, D ₂ O) δ ppm 7.54-7.58 (t, 1H), 7.75-7.77 (d, 1H), 8 10-8.12 (d, 1H); 8.23 (S, 1H). LCMS (ESI) mass / charge: 226 (M + 1).

Example 39

3- (Aminomethyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

To a mixture of Example 37D (100 mg, 0.4 mmol) in DCM (20 ml) and MeOH (50 ml) were added NiCl ₂ -6H ₂ O (200 mg, 0.8 mmol) and NaBH ₄ (47 mg, 1) in portions. , 2 mmol). After stirring at 0 ° C for 5 min, the reaction mixture was evaporated to give a residue, which was purified by preparative HPLC to give the title compound (45 mg, 45%). ¹ H NMR (400 MHz, D ₂ O) ppm 4.2 (S, 2H), 7.269-7.318 (t, 2H), 7.796 (S, 1H), 8.399 (S, 1H). LCMS (ESI) mass / charge: 248 (M + 1).

Example 40

3- (Cyclopropanecarboxamidomethyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 39 (20 mg, 0.081 mmol), cyclopropanecarboxylic acid (8.36 mg, 0.098 mmol), HOBt (13.12 mg, 0.0979 mmol), EDCI (18.61 mg, 0.097 mmol) and Et ₃ N (25 mg, 0.242 mmol) in DMF (5 ml) was stirred at 30 ° C for 6 hours. After removal of the solution in vacuo, the residue was purified by preparative HPLC to give the title compound (11.9 mg, 48%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.64-0.72 (m, 4H), 1.52-1.57 (m, 1H), 4.25-2.50 (d, 2H), 7.57-7.61 (m, 2H), 7.82 (s, 1H), 8.13 (s, 1H), 8.44-8.46 (t, 1H), 10.46 (s, 1H); 11.93 (br, 1H). LCMS (ESI) mass / charge: 316 (M + 1).

Scheme B

Example 41

6-Fluoro-3- (4-fluorophenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 41A

Ethyl 5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazole-4-carboxylate

A mixture of Example 1D (5 g, 17.61 mmol) and ethyl 2-cyano-3-ethoxyacrylate (2.98 g, 17.61 mmol) in EtOH (100 ml) was stirred at 78 ° C. for 16 hours. After removing the solution under vacuum, the residue was purified by column chromatography to give the title compound (2.7 g, yield: 38%), which could be used directly in the next step without further purification.

Example 41B

Ethyl 8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carboxylate

The mixture of example 41A (2.7 g, 6.63 mmol), CuI (252 mg, 1.33 mmol), N ¹ , N ^2- dimethylethane-1,2-diamine (233.9 mg, 2.65 mmol) and K ₃ PO ₄ (4.22 g, 19.9 mmol) in DMF (60 ml) was stirred at 70 ° C. for 16 hours under N ₂ atmosphere. After cooling to room temperature, the mixture was filtered and the solvent was evaporated in vacuo. The resulting residue (2.16 g) could be used directly in the next step without further purification.

Example 41C

8-Bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carboxylic acid

A mixture of Example 41B (2.16 g, 6.62 mmol) and NaOH (1.06 g, 26.49 mmol) in MeOH (40 ml) and H ₂ O (10 ml) was stirred at 70 ° C. for 16 hours After evaporation of the solvent, the resulting residue could be used directly in the next step without further purification.

Example 41D

8-Bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole

A solution of Example 41C (1.97 g, 6.61 mmol) in a mixture of concentrated HCl (20 ml) and H ₂ O (20 ml) was stirred at 80 ° C for 16 hours. After neutralization with concentrated NH ₄ OH, obtained in as a result, the mixture was filtered. The precipitate was washed with MeOH and dried under vacuum. The resulting solid (1.58 g) could be used directly in the next step without further purification.

Example 41E

8-Bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole

To a solution of NaH (0.746 g, 18.66 mmol) in THF (10 ml) was added a solution of Example 41D (1.58 g, 6.22 mmol) in THF (20 ml) at 0 ° C. under N ₂ . The mixture was stirred at 0 ° C. for 0.5 h, and then SEMCl (1.56 g, 9.33 mmol) was added thereto. The mixture was stirred at 0 ° C for another 1 h, and then quenched with water (20 ml). The aqueous layer was extracted with DCM (20 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (0.43 g, yield: 17% in 4 steps). LCMS (ESI) mass / charge: 384, 386 (M, M + 2).

Example 41F

Methyl-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxylate

The mixture of example 41E (0.43 g, 1.12 mmol), Pd (OAc) ₂ (50 mg, 0.233 mmol), Pd (dppf) Cl ₂ (164 mg, 0.233 mmol), xanthos (194 mg, 0.335 mmol) , DPPP (138 mg, 0.335 mmol), PPh ₃ (88 mg, 0.335 mmol) and Et ₃ N (566 mg, 5.59 mmol) in DMF (10 ml) and MeOH (10 ml) were stirred at 80 ° C in for 24 hours in a CO atmosphere (3 atm). After cooling to room temperature, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (0.265 g, yield: 63%). LCMS (ESI) mass / charge: 364 (M + 1).

Example 41G

Methyl-3-bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxylate

A mixture of Example 41F (0.265 g, 729 mmol) and NBS (117 mg, 656 mmol) in DCM (20 ml) was stirred at 10 ° C for 20 minutes. After removing the solution in vacuo, the residue was purified by column chromatography to give the title compound (0.24 g, yield: 75%). LCMS (ESI) mass / charge: 442, 444 (M, M + 2).

Example 41H

3-Bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxylic acid

A mixture of Example 41G (240 mg, 0.542 mmol) and NaOH (108 mg, 2.71 mmol) in MeOH (6 ml) and H ₂ O (1.5 ml) was stirred at 60 ° C. for 0.5 h. After cooling to room temperature, the mixture was adjusted to pH 4 with 1N. HCl, and the aqueous phase was extracted with EtOAc (20 ml × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and evaporated to give the title compound (196 mg, yield: 84%), which was used directly in the next step without further purification.

Example 41I

3-Bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 41H (0.196 g, 0.46 mmol), HATU (0.226 mg, 0.595 mmol), (NH ₄ ) ₂ CO ₃ (0.439 g, 4.6 mmol) and Et ₃ N (0.138 g, 1.37 mmol) ) in DMF (8 ml) was stirred at 40 ° C for 16 hours in an atmosphere of N ₂ . After removing the solution under vacuum, the residue was diluted with water (10 ml). The aqueous layer was extracted with EtOAc (15 ml × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography to give the title compound (0.125 g, yield: 64%). LCMS (ESI) mass / charge: 427, 429 (M, M + 2).

Example 41J

6-Fluoro-3- (4-fluorophenyl) -4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 41I (50 mg, 0.117 mmol), Pd (dppf) Cl ₂ (17 mg, 0.023 mmol), Na ₂ CO ₃ (31 mg, 0.292 mmol) and (4-fluorophenyl) boric acid (24 mg, 0.175 mmol ) in DMF (3 ml) and H ₂ O (0.5 ml) was stirred at 100 ° C for 16 hours in an atmosphere of N ₂ . After removing the solution under vacuum, the residue was diluted with water (10 ml). The aqueous layer was extracted with EtOAc (10 ml × 3). The combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered and evaporated. The residue was purified by preparative TLC to give the title compound (40 mg, yield: 77%). LCMS (ESI) mass / charge: 443 (M + 1).

Example 41K

6-Fluoro-3- (4-fluorophenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 41J (40 mg, 0.090 mmol) in TFA (0.5 ml) and DCM (0.5 ml) was stirred at 10 ° C. for 5 hours. After removal of the solution in vacuo, MeOH (3 ml) was added to the residue and K ₂ CO ₃ (0.037 g, 0.271 mmol). The mixture was stirred at 10 ° C. for 2 hours. The mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound (6.3 mg, yield: 24%). ¹ H NMR (400 MHz, DMSO-d6) δ: 8.32 (s, 1H), 7.67-7.71 (m, 2H), 7.59-7.61 (d, 1H), 7, 55-7.57 (d, 1H); 7.22-7.27 (t, 2H). LCMS (ESI) mass / charge: 313 (M + 1).

Example 42

6-Fluoro-3- (2-fluoro-4 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 42A

1- (4-Bromo-3-fluorophenyl) -N-methylmethanamine

A mixture of 4-bromo-3-fluorobenzaldehyde (2 g, 9.8 mmol) and methanamine (30-40% in EtOH) (10 ml, 16.7 mmol) in EtOH (10 ml) was stirred at 75 ° C for 15 h. The mixture was cooled to room temperature, and then NaBH ₄ (745 mg, 19.6 mmol) was added to it in one portion and stirred for another 30 minutes. After removing the solution under vacuum, the residue was diluted with saturated NaHCO ₃ (20 ml). The aqueous layer was extracted with EtOAc (50 ml × 3). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (1.47 g, yield: 74%). LCMS (ESI) mass / charge: 218, 220 (M, M + 2).

Example 42B

tert-butyl- (4-bromo-3-fluorobenzyl) (methyl) carbamate

A mixture of example 42A (1.47 g, 6.77 mmol), Boc ₂ O (1.77 g, 8.12 mmol) and Et ₃ N (1.37 g, 13.54 mmol) in DCM (15 ml) stirred at 18 ° C. for 2 hours. After removing the solution in vacuo, the residue was purified by column chromatography to give the title compound (1.83 g, yield: 85%). LCMS (ESI) mass / charge: 319 (M + 1).

Example 42C

tert-Butyl- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) (methyl) carbamate

A mixture of 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl-2.2'-bi (1,3,2-dioxaborolan) (1.76 g, 6.92 mmol), Example 42B (1.83 g, 5.77 mmol), KOAc (1.13 g, 11.54 mmol) and Pd (dppf) Cl ₂ (422 mg, 0.577 mmol) in DMSO (15 ml) were stirred at 80 ° C for 15 hours in an atmosphere of N ₂ . After cooling to room temperature, the mixture was filtered and the filtrate was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (50 ml × 2). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (2 g, yield: 95%) as colorless oils.

Example 42D

tert-Butyl- (4- (8-carbamoyl-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3- il) -3-fluorobenzyl) (methyl) carbamate

A mixture of example 41I (100 mg, 0.23 mmol), example 42C (85.7 mg, 0.23 mmol), Na ₂ CO ₃ (50 mg, 0.47 mmol) and Pd (dppf) Cl ₂ (17, 1 mg, 0.023 mmol) in DMF (5 ml) and H ₂ O (1 ml) was stirred at 80 ° C for 15 h in an atmosphere of N ₂ . After cooling to room temperature, the mixture was filtered and the filtrate was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (50 ml × 2). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by preparative TLC to give the title compound (110 mg, yield: 97%). LCMS (ESI) mass / charge: 586 (M + 1).

Example 42E

6-Fluoro-3- (2-fluoro-4 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 42D (110 mg, 0.19 mmol) in TFA (5 ml) and DCM (5 ml) was stirred at 10 ° C for 15 hours. After removal of the solution in vacuo, MeOH (15 ml) and K ₂ were added to the residue. CO ₃ (53 mg, 0.38 mmol). The mixture was stirred at 18 ° C. for 15 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between water (10 ml) and EtOAc (10 ml). The aqueous layer was extracted with EtOAc / THF = 3 / l (20 ml × 2). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by preparative HPLC to give the title compound (22.45 mg, yield: 34%) as a white solid . ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 2.79 (s, 3H), 4.24 (s, 2H), 4.48-5.29 (m, 27 N), 7.37-7 43 (m, 2H), 7.52 (d, J = 7.78 Hz, 1H), 7.72 (d, J = 9.79 Hz, 1H), 7.78 (t, J = 7, 78 Hz, 1H), 8.23 (s, 1H), 8.49 (br.s., 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 43

6-Fluoro-3- (4 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 42. ¹ H-NMR (400 MHz, methanol-d ₄ + D ₂ O) 2.77 (s, 3H), 4.21 (s, 2H), 7.46- 7.62 (m, 3H), 7.75 (d, J = 8.16 Hz, 3H), 8.26 (s, 1H), 8.53 (br.s., 1H). LCMS (ESI) mass / charge: 338 (M + 1).

Example 44

6-Fluoro-3- (2-fluoro-5 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 42. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) 2.59 (br.s., 3H), 4.13 (br.s., 2H ), 7.15-7.41 (m, 2H), 7.47-7.68 (m, 2H), 7.95-8.09 (m, 1H), 8.16-8.27 (m , 1H); 8.36 (br.s., 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 45

6-Fluoro-3- (pyridin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 42. ¹ H-NMR (MeOD, 400 MHz) δ: 7.55-7.63 (m, 2H), 7.73-7.79 (m, 1H), 8 11-8.14 (m, 1H), 8.15-8.19 (m, 1H), 8.48-8.54 (m, 2H), 8.55-8.59 (m, 1H) 10.28-10.36 (m, 1H). LCMS (ESI) mass / charge: 296 (M + 1).

Example 46

6-Fluoro-3- (4- (piperidin-3-yl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 46A

tert-Butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate

Mixture of tert-Butyl 3- (4-aminophenyl) piperidine-1-carboxylate (0.1 g, 0.362 mmol), 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl-2 , 2'-bi (1,3,2-dioxaborolan) (0.101 g, 0.398 mmol), BPO (1.75 g, 0.00724 mmol) and tert-BuONO (0.056 g, 0.542 mmol) in acetonitrile (3 ml ) was stirred at 10 ° C for 16 h in an atmosphere of N ₂ . The solvent was evaporated in vacuo and the residue was purified by preparative TLC to give the title compound (0.095 g, yield: 68%).

Example 46B

6-Fluoro-3- (4- (piperidin-3-yl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 42. ¹ H NMR (300 MHz, methanol-d ₄ ) ppm 1.189 (m, 2H), 2.10-2.01 (m, 2H), 3.03-3, 14 (m, 3H), 3.45-3.49 (m, 2H), 7.37-7.40 (d, 2H), 7.44-7.47 (dd, 1H), 7.66- 7.68 (d, 2H), 7.74-7.79 (dd, 1H), 8.22 (s, 1H), 8.53 (s, 1H). LCMS (ESI) mass / charge: 378 (M + 1).

Example 47

6-Fluoro-3- (tetrahydro-2H-pyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 47A

3.6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate

To a solution of dihydro-2H-pyran-4 (3H) -one (1.8 g, 18.0 mol) in THF (20 ml) was added LiHMDS (1 M, 21.6 ml, 21.6 mmol) at -78 ° C in an atmosphere of N ₂ . After stirring for 1 h at −78 ° C., (CF ₃ SO ₂ ) ₂ NPh (6.4 g, 18.0 mmol) was added in portions. The mixture was stirred at 15 ° C. for 16 hours and quenched with aq. NH ₄ Cl solution (20 ml). The aqueous layer was extracted with EtOAc (30 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a colorless oil (1.5 g, yield: 35.7%). LCMS (ESI) mass / charge: 233 (M + 1).

Example 47B

2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan

This example was obtained according to the method described in example 42C.

Example 47C

6-Fluoro-3- (tetrahydro-2H-pyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 46B. ¹ H-NMR (MeOD, 400 MHz) δ: 1.82-2.03 (m, 4H), 2.93-3.04 (m, 1H), 3.62 (td, J = 11.70, 2.45 Hz, 2H), 4.04-4.11 (m, 2H), 7.32-7.39 (m, 1H), 7.66-7.75 (m, 2H), 8.51 -8.55 (m, 1H). LCMS (ESI) mass / charge: 303 (M + 1).

Example 48

3- (4- (Dimethylamino) cyclohexyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 48A

4 - ((Tert-butoxycarbonyl) amino) cyclohex-1-en-1-yl-trifluoromethanesulfonate

To a solution of tert-butyl- (4-oxocyclohexyl) carbamate (1 g, 4.698 mol) in THF (20 ml) was added dropwise LiHMDS (1 M, 9.4 ml, 9.378 mmol) at -78 ° C in an atmosphere of N ₂ . After stirring at -78 ° C for 1 h, a solution of (CF ₃ SO ₂ ) ₂ NPh (1.84 g, 5.158 mmol) in THF (5 ml) was added. The mixture was stirred at 15 ° C for 16 hours and then quenched with aq. NH ₄ Cl solution (20 ml). The aqueous layer was extracted with EtOAc (20 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (1.16 g, yield: 71.60%). LCMS (ESI) mass / charge: 347 (M + 1).

Example 48B

tert-Butyl- (4- (4.4,5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) carbamate

This example was obtained according to the method described in example 47B.

Example 48C

3- (4-Dimethylamino) cyclohexyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the methods described in example 47C and example 2. ¹ H-NMR (MeOD, 400 MHz) δ: 1.63-1.87 (m, 3H), 1.91-2.10 (m, 2H ), 2.20-2.46 (m, 3H), 2.81 (s, 4H), 2.90 (s, 3H), 3.19-3.30 (m, 1H), 7.34- 7.44 (m, 1H), 7.64-7.75 (m, 2H), 7.78-7.85 (m, 1H), 8.38-8.73 (m, 3H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 49

6-Fluoro-3- (4-methylpiperazin-1-carbonyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 49A

Ethyl 8-bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carboxylate

To a solution of Example 41B (3.2 g, 9.812 mol) in THF (50 ml) was added NaH (785 mg, 19.625 mmol) in portions at 0 ° C. under N ₂ . After stirring at 15 ° C for 0.5 h and cooling to 0 ° C, SEMC1 (3.3 g, 19.625 mmol) was added dropwise to it. The mixture was stirred at 15 ° C for another 16 hours, and then quenched with saturated aq. NH ₄ Cl solution (30 ml). The aqueous layer was extracted with EtOAc (30 ml × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography to give the title compound as a yellow solid (2.16 g, yield: 48.21%). LCMS (ESI) mass / charge: 456, 458 (M, M + 2).

Example 49B

8-Bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carboxylic acid

A mixture of example 49A (2.16 g, 4.726 mmol) and NaOH (950 mg, 23.632 mmol) in a mixed solvent of MeOH / H ₂ O (2: 1) (30 ml) was stirred at 80 ° C for 16 hours. The resulting the mixture was adjusted to pH 3-4 with 1N. Hcl. The aqueous layer was extracted with EtOAc (30 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and evaporated to give the title compound (1.73 g, yield: 85.22%) which could be used in the next step without further purification.

Example 49C

tert-Butyl-4- (8-bromo-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carbonyl ) piperazine-1-carboxylate

A mixture of tert-butyl piperazine-1-carboxylate (415 mg, 2.241 mmol), Example 49B (800 mg, 1.868 mmol), HATU (1.42 g, 3.735 mmol) and Et ₃ N (567 mg, 5.603 mmol) in DMF (15 ml) was stirred at 15 ° C for 16 hours in an atmosphere of N ₂ . The mixture was quenched with H ₂ O (10 ml). The aqueous layer was extracted with EtOAc (20 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography to give the title compound (1 g, yield: 90%). LCMS (ESI) mass / charge: 596, 598 (M, M + 2).

Example 49D

tert-Butyl-4- (8-cyano-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carbonyl ) piperazine-1-carboxylate

A mixture of Example 49C (400 mg, 0.671 mmol), Zn (87 mg, 1.341 mmol), Zn (CN) ₂ (158 mg, 1.341 mmol), DPPF (75 mg, 0.134 mmol) and Pd ₂ (DBA) ₃ (61 mg, 0.0671 mmol) in DMF (10 ml) was stirred at 120 ° C. under N ₂ for 10 hours. After cooling to room temperature, the resulting mixture was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (30 ml × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (350 mg, yield: 96.15%). LCMS (ESI) mass / charge: 543 (M + 1).

Example 49E

tert-Butyl-4- (8-carbamoyl-6-fluoro-4 - ((2- (trimethylsilyl) ethoxy) methyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-3-carbonyl ) piperazine-1-carboxylate

To the mixture of Example 49D (400 mg, 0.737 mmol) and K ₂ CO ₃ (510 mg, 3.685 mmol) in DMSO (10 ml) was added H ₂ O ₂ (5 ml) at 0-5 ° C. After completion of the dropwise addition, the mixture was stirred at 15 ° C for 1 h and quenched with aq. Na ₂ SO ₃ solution (20 ml). The aqueous layer was extracted with EtOAc (30 ml × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography to give the title compound (400 mg, yield: 96.85%). LCMS (ESI) mass / charge: 561 (M + 1).

Example 49F

6-Fluoro-3- (piperazine-1-carbonyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 49E (100 mg, 0.178 mmol) in TFA (1 ml) and DCM (1 ml) was stirred at 15 ° C for 16 hours. After removal of the solution in vacuo, K ₂ CO ₃ (123 mg, 0.892 mmol) was added to the residue. and MeOH (2 ml). The mixture was stirred at 15 ° C for 2 hours. The mixture was filtered and the filtrate was evaporated to give the title compound, which could be used directly in the next step without further purification.

Example 49G

6-Fluoro-3- (4-methylpiperazin-1-carbonyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 49F (59 mg, 0.179 mmol), formaldehyde (40 mg, 0.358 mmol) and Na (CN) BH ₃ (56 mg, 0.894 mmol) in MeOH (2 ml) was stirred at 15 ° C for 16 hours. After evaporating the solvent in vacuo the residue was purified by preparative HPLC to give the title compound (8.14 mg, yield: 13.23%) as a white solid. ¹ H-NMR (MeOD, 400 MHz) δ: 2.68 (s, 3H), 2.99 (d, J = 4.64 Hz, 4H), 4.00 (br.s., 4H), 7 , 46-7.54 (m, 1H), 7.74-7.84 (m, 1H), 8.12-8.20 (m, 1H), 8.24-8.35 (m, 2H) . LCMS (ESI) mass / charge: 345 (M + 1).

Example 50

3- (1- (Cyclopropylmethyl) piperidin-4-yl) -4,4,6-trifluoro-4H-pyrazolo [1,5-α] indole-8-carboxamide

Example 50A

Ethyl (E) -4- (dimethylamino) -2-oxobut-3-enoate

A solution of ethyl 2-oxopropanoate (5.0 g, 43.1 mmol) in DMF-DMA (5.0 g, 42.0 mmol) was stirred at 20 ° C. for 16 hours. The resulting mixture was evaporated to give the title compounds (7.0 g, crude) as a brown oil, which could be used directly in the next step without further purification.

Example 50B

Ethyl 1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazole-5-carboxylate

A mixture of Example 1D (5.0 g, 17.6 mmol), Example 50A (6.0 g, 35.2 mmol) in EtOH (100 ml) and conc. HCl (2.4 ml) was stirred at 80 ° C. for 16 hours. After removal of the solution in vacuo, the residue was purified by column chromatography to give the title compound (3.6 g, yield: 46.8%) as a yellow solid.

Example 50C

1- (2,6-Dibromo-4-fluorophenyl) -1H-pyrazole-5-carboxylic acid

A mixture of Example 50B (3.6 g, 9.18 mmol) and NaOH (2.2 g, 55.1 mmol) in MeOH (20 ml) and water (2 ml) was stirred at 20 ° C for 1 h. After removing the solution under vacuum, the residue was diluted with water (50 ml) and adjusted to pH 3 with 2 N. Hcl. The aqueous layer was extracted with dichloromethane (50 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (3.2 g, 97.0%), which could be used directly in the next step without further purification.

Example 50D

1- (2,6-Dibromo-4-fluorophenyl) -N-methoxy-N-methyl-1H-pyrazole-5-carboxamide

A mixture of Example 50C (3.2 g, 8.82 mmol), O, N-dimethyl-hydroxylamine (1.7 g, 17.6 mmol), HATU (4.0 g, 10.6 mmol) and Et ₃ N (3.6 g, 35.3 mmol) in dry DMF (2 ml) was stirred at 20 ° C for 16 h in an atmosphere of N ₂ . After removing the solution under vacuum, the residue was purified by column chromatography to give the title compound (3.4 g, yield: 94.4%) as a yellow solid.

Example 50E

8-Bromo-6-fluoro-4H-pyrazolo [1,5-a] indol-4-one

To a mixture of Example 50D (3.2 g, 7.90 mmol) in dry THF (5 ml), n-BuLi (2.8 ml, 7.11 mmol) was added dropwise at −78 ° C. under N ₂ . After stirring at -78 ° C for 0.5 h, the mixture was quenched with sat. aq. NH ₄ Cl solution (30 ml).

The aqueous layer was extracted with DCM (50 ml × 2). The combined organic layers were evaporated. The residue was washed with MeOH (30 ml) to give the title compound (1.5 g, yield: 71.4%) as a bright yellow solid. LCMS (ESI) mass / charge: 267, 269 (M, M + 2).

Example 50F

Methyl-6-fluoro-4-oxo-4H-pyrazolo [1,5-a] indole-8-carboxylate

A mixture of Example 50E (1.3 g, 4.89 mmol), Pd (dppf) Cl ₂ (0.71 g, 0.98 mmol), Pd (OAc) ₂ (0.22 g, 0.98 mmol), DPPP (0.81 g, 1.96 mmol), PPh ₃ (0.51 g, 1.96 mmol), xanthos (1.13 g, 1.96 mmol) and Et ₃ N (3 ml) in MeOH ( 20 ml) and DMF (60 ml) were stirred at 80 ° C for 16 h in a CO atmosphere (3 atm). After cooling to 20 ° C., the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (0.9 g, yield: 75.0%) as a yellow solid. LCMS (ESI) mass / charge: 247 (M + 1).

50G example

Methyl 6-fluorospiro [pyrazolo [1,5-a] indole-4,2 '- [1,3] dithiolane] -8-carboxylate

A mixture of Example 50F (0.9 g, 3.66 mmol), 2-ethanedithiol (0.69 g, 7.32 mmol) and BF ₃ -Et ₂ O (1.0 g, 7.32 mmol) in dry DCM (30 ml) was stirred at 50 ° C for 24 hours in an atmosphere of N ₂ . After cooling to room temperature, the mixture was diluted with DCM (30 ml). The combined organic layers were washed with 10% NaOH (30 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to obtain the title compound (0.5 g, yield: 42.4%) as a yellow solid. LCMS (ESI) mass / charge: 323 (M + 1).

Example 50H

Methyl 3-bromo-6-fluorospiro [pyrazolo [1,5-a] indole-4,2 '- [1,3] dithiolane] -8-carboxylate

A mixture of Example 50G (500 mg, 1.55 mmol) and NBS (276 mg, 1.55 mmol) in THF (20 ml) was stirred at 40 ° C. for 16 hours. After cooling to 20 ° C., the mixture was evaporated and the residue purified by column chromatography to give the title compound (470 mg, yield: 75.7%) as a light yellow solid. LCMS (ESI) mass / charge: 401, 403 (M, M + 2).

Example 50I

Methyl 3-bromo-4,4,6-trifluoro-4H-pyrazolo [1,5-a] indole-8-carboxylate

Methyl 3-bromo-6-fluoro-4-oxo-4H-pyrazolo [1,5-a] indole-8-carboxylate

To a solution of NIS (2.1 g, 9.38 mmol) in DCM (20 ml) was added dropwise HF.Py (3.5 ml) at −78 ° C. under N ₂ . After stirring at -78 ° C for 10 min, Example 50H (470 mg, 1.17 mmol) was added. The resulting mixture was stirred at -78 ° C for 16 hours and then quenched with sat. aq. NaHCO ₃ solution (30 ml). The aqueous layer was extracted with EtOAc (30 ml × 2). The combined organic layers were washed with sat. aq. Na ₂ SO ₃ solution (30 ml), and the solvent was evaporated in vacuo. The residue was purified by column chromatography to give Example 50IA as a yellow solid (250 mg, yield: 61.6%) and to give Example 50IB (110 mg, yield: 27.2%) as a white solid.

Example 50J

3- (1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -4,4,6-trifluoro-4H-pyrazolo [1,5-a] indole-8-carboxylic acid

A mixture of example 50IA (200 mg, 0.499 mmol), tert-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H ) -carboxylate (185 mg, 0.598 mmol), Pd (dppf) Cl ₂ (37 mg, 0.050 mmol) and K ₂ CO ₃ (138 mg, 0.997 mmol) in DMF (9 ml) and H ₂ O (3 ml) stirred at 90 ° C for 16 hours in an atmosphere of N ₂ . After the mixture was cooled to room temperature and concentrated in vacuo, the residue was dissolved in water (20 ml) and adjusted to pH 3 with 1N. HCl. The aqueous layer was extracted with DCM (50 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (220 mg, crude) without further purification.

Sample 50K

tert-Butyl 4- (8-carbamoyl-4,4,6-trifluoro-4H-pyrazolo [1,5-a] indol-3-yl) -5,6-dihydropyridin-1 (2H) -carboxylate

A mixture of Example 50J (220 mg, 0.51 mmol), (NH ₄ ) ₂ CO ₃ (97 mg, 1.01 mmol), Et ₃ N (0.2 ml, 1.53 mmol) and HATU (252 mg, 0.66 mmol) in DMF (8 ml) was stirred at 20 ° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title compound as a yellow solid (70 mg, yield: 32.0 %). LCMS (ESI) mass / charge: 435 (M + 1).

Example 50L

tert-Butyl-4- (8-carbamoyl-4,4.6-trifluoro-4H-pyrazolo [1,5-a] indol-3-yl) piperidine-1-carboxylate

A mixture of Example 50K (35 mg, 0.08 mmol) and 10% Pd / C (20 mg) in dry DCM (20 ml) and MeOH (10 ml) were hydrogenated at 50 ° C. for 16 hours in an H ₂ atmosphere (1 atm). The mixture was filtered and the filtrate was evaporated to give the title compound (30 mg, yield: 85.7%), which could be used directly in the next step without further purification. LCMS (ESI) mass / charge: 437 (M + 1).

Example 50M

4,4,6-Trifluoro-3- (piperidin-4-yl) -4H-pyrazolo [1,5-a] indole-8-carboxamide

A mixture of Example 50L (200 mg, 0.466 mmol) in TFA (2 ml) and DCM (6 ml) was stirred at 20 ° C. for 2 hours. The resulting mixture was evaporated to give the title compound, which could be used directly in the next step. without further purification (30 mg, crude).

Example 50N

3- (1- (Cyclopropylmethyl) piperidin-4-yl) -4,4,6-trifluoro-4H-pyrazolo [1,5-α] indole-8-carboxamide

A mixture of Example 50M (30 mg, 0.069 mmol), cyclopropanecarbaldehyde (10 mg, 0.138 mmol), Ti (O-ipr) ₄ (39 mg, 0.138 mmol) and Na (CN) BH ₃ (13 mg, 0.207 mmol) in MeOH (8 ml) was stirred at 60 ° C for 16 h in an atmosphere of N ₂ . The resulting mixture was quenched with water (10 ml). The aqueous layer was extracted with DCM (20 ml × 3). The combined organic layers were evaporated and the residue was purified by preparative HPLC to give the title compound as a white solid (5 mg, yield: 18.5%). ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.41 (d, J = 4.89 Hz, 2H), 0.72-0.81 (m, 2H), 1.13 (br. s., 1H), 1.93-2.13 (m, 2H), 2.31 (d, J = 13.93 Hz, 2H), 2.87-3.12 (m, 5 N), 3 66 (d, J = U, 17 Hz, 2H), 7.78-7.82 (m, 1H), 7.85 (s, 1H), 7.97 (dd, J = 9.91, 2 64 Hz, 1H); 8.07 (s, 1H). LCMS (ESI) mass / charge: 391 (M + 1).

Example 51

3- (1-Ethylpiperidin-4-yl) -6-fluoro-4-hydroxy-4H-pyrazolo [1,5-a] indole-8-carboxamide

Example 51A

tert-Butyl-4- (8-carbamoyl-6-fluoro-4-oxo-4H-pyrazolo [1,5-a] indol-3-yl) -3,6-dihydropyridin-1 (2H) -carboxylate

This example was obtained as described in example 50K. LCMS (ESI) mass / charge: 413 (M + 1).

Example 51B

tert-Butyl-4- (8-carbamoyl-6-fluoro-4-hydroxy-4H-pyrazolo [1,5-a] indol-3-yl) piperidine-1-carboxylate

A mixture of Example 51A (50 mg, 0.121 mmol) and 10% Pd / C (10 mg) in dry MeOH (10 ml) was hydrogenated at 50 ° C. for 16 hours in an H ₂ atmosphere (1 atm). The mixture was filtered and the filtrate was evaporated to give the title compound (40 mg, yield: 80.0%), which could be used directly in the next step without further purification. LCMS (ESI) mass / charge: 417 (M + 1).

Example 51C

6-Fluoro-4-hydroxy-3- (piperidin-4-yl) -4H-pyrazolo [1,5-a] indole-8-carboxamide

This example was obtained as described in example 50M.

Example 51D

3- (1-Ethylpiperidin-4-yl) -6-fluoro-4-hydroxy-4H-pyrazolo [1,5-a] indole-8-carboxamide

A mixture of Example 51C (25 mg, 0.079 mmol), 40% acetaldehyde (0.1 ml) and Na (CN) BH ₃ (20 mg, 0.316 mmol) in MeOH (5 ml) was stirred at 10 ° C for 16 hours. The resulting mixture was diluted with water (10 ml). The aqueous layer was extracted with DCM (20 ml × 3). The combined organic layers were evaporated to give a residue, which was purified by preparative HPLC to give the title compound (9.40 mg, yield: 34.8%) as a white solid. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.11-1.18 (m, 3H), 1.77-1.96 (m, 2H), 2.01-2.16 (m , 2H), 2.61 (br.s., 2H), 2.81 (br.s., 3H), 3.27 (br.s., 2H), 5.72 (s, 1H), 7 59 (dd, J = 7.22, 2.45 Hz, 1H), 7.70 (d, J = 10.42 Hz, 1H), 7.76 (s, 1H), 7.99 (br. s., 1H), 8.32 (br.s., 1H), 10.09 (br.s., 1H). LCMS (ESI) mass / charge: 345 (M + 1).

Example 52

3- (1-Ethylpiperidin-4-yl) -6-fluoro-4-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 52A

tert-Butyl-4- (8-carbamoyl-6-fluoro-4-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) piperidine-1-carboxylate

A mixture of Example 1I (30 mg, 0.075 mmol), K ₂ CO ₃ (31 mg, 0.224 mmol) and CH ₃ I (32 mg, 0.224 mmol) in DMF (3 ml) was stirred at 10 ° C. for 1 h. Reaction the mixture was quenched with water (10 ml). The aqueous layer was extracted with EtOAc (10 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound, which could be used directly in the next step without further purification.

Example 52B

6-Fluoro-4-methyl-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 52A (31 mg, 0.074 mmol) in DCM (1 ml) and TFA (0.2 ml) was stirred at 10 ° C. for 2 hours. The mixture was evaporated to give the title compound, which could be used directly in the next step without additional cleaning.

Example 52C

3- (1-Ethylpiperidin-4-yl) -6-fluoro-4-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 51D. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.23-1.26 (t, 3H), 1.91-1.97 (m, 2H), 2.11-2.14 (d , 2H), 2.55 (t, 2H), 2.78-2.80 (m, 2H), 3.04-3.07 (m, 2H), 3.32 (2H), 3.87 ( s, 2H), 7.48-8.50 (m, 1H), 7.64-7.67 (m, 1H), 7.73 (s, 1H), 8.54 (s, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Scheme C

Example 53

6-Fluoro-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 53A

1- (tert-Butyl) -4-methyl-4-methylpiperidin-1,4-dicarboxylate

To a solution of 1-tert-butyl-4-methyl-piperidine-1,4-dicarboxylate (36.5 g, 0.15 mol) in anhydrous THF (400 ml) was added dropwise LiHMDS (1 M, 300 ml) at - 78 ° C in an atmosphere of N ₂ . After stirring at -78 ° C for 30 minutes, a solution of Mel (42.6 g, 0.3 mol) in THF (100 ml) was added dropwise thereto. The reaction mixture was stirred at -78 ° C for 2 hours, and heated to 15 ° C, and stirred for an additional 20 hours. After completion of the reaction, the mixture was quenched with sat. aq. NH ₄ Cl solution (500 ml). The aqueous layer was extracted with EtOAc (500 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (30 g, yield: 78%). LCMS (ESI) mass / charge: 258 (M + 1).

Example 53B

tert-butyl-4- (hydroxymethyl) -4-methylpiperidin-1-carboxylate

To a solution of LiAlH ₄ (3.7 g, 97.5 mmol) in anhydrous THF (40 ml) was added dropwise a solution of Example 53A (10 g, 39 mmol) in anhydrous THF (80 ml) at 0 ° C. under N ₂ . After completion of the dropwise addition, the reaction mixture was stirred at 0 ° C for 2.5 hours, and then quenched with water (4 ml), 15% aq. NaOH solution (4 ml) and water (12 ml). The resulting mixture was stirred at 0 ° C for an additional 20 minutes. The mixture was filtered and the solid was washed with EtOAc (50 ml × 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (9 g, crude), which could be used directly in the next step without further purification.

Example 53C

tert-Butyl 4- (cyanomethyl) -4-methylpiperidin-1-carboxylate

This example was obtained according to the method described in examples 1A-1B.

Example 53D

6-Fluoro-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1E-1J. ¹ H NMR (400 MHz, MeOD) δ: 8.51 (s, 1H), 7.81 (s, 1H), 7.69 (dd, J = 2.4 Hz / t = 10.2 Hz, 1H ), 7.45 (dd, J = 2.4 HzL = 8.0 Hz, 1H), 3.33-3.39 (m, 2H), 3.12-3.32 (m, 2H), 2 42-2.46 (m, 2H); 2.03-2.08 (m, 2H); 1.46 (s, 3H). LCMS (ESI) mass / charge: 316 (M + 1).

Example 54

3- (1-Ethyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 52C (10 mg, yield: 38%). ¹ H NMR (400 MHz, DMSO) δ: 10.58 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.61 (dd, J = 2.8 Hz / J = 7.2 Hz, 1H), 7.49 (t, J = 2.4 Hz, 1H), '2.75-2.78 (m, 2H), 2.50-2.54 (m, 4H), 2.18-2.20 (m, 2H), 1.73-1.78 (m, 2H), 1.30 (s, 3H), 1, 05 (t, J = 7.2 Hz, 3H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 55

3- (1-Cyclopropyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 4. ¹ H-NMR (400 MHz, methanol-d ₄ ) 0.77 (d, J = 5.40 Hz, 4H), 1.41-1.45 (m, 3H ), 1.90-2.01 (m, 2H), 2.28-2.44 (m, 3H), 3.03 (br.s., 2H), 3.27 (br.s., 2H) ), 7.39 (dd, J = 8.16, 2.51 Hz, 1H), 7.73 (dd, J = 10.92, 2.38 Hz, 1H), 7.79 (s, 1H) 8.41 (br.s., 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 56

6-Fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 6. ¹ H-NMR (400 MHz, DMSO-d ₄ ) δ ppm 1.13 (s, 6H), 1.28 (s, 3H), 1.86 (t, J = 10.23 Hz, 2H), 2.20 (d, J = 15.43 Hz, 2H), 2.62 (s, 2H), 2.76 (br.s., 2H), 3.04 (d, J = 4.02 Hz, 2H), 7.48 (dd, J = 8.34, 2.57 Hz, 1H), 7.56 (dd, J = 10.92, 2.64 Hz, 1H), 7.79 (s, 1H), 8.31 (s, 1H). LCMS (ESI) mass / charge: 388 (M + 1).

Example 57

3- (1- (Cyclopropylmethyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 5. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.37 (d, J = 3.89 Hz, 2H), 0.73 (d, J = 7.53 Hz, 2H), 1.02-1.14 (m, 1H), 1.44 (br.s., 3H), 2.08 (d, J-11.29 Hz, 2H), 2 37-2.66 (m, 2H), 2.94 (br.s., 3H), 3.34-3.63 (m, 3H), 7.38 (dd, J = 8.09, 2 , 57 Hz, 1H), 7.71 (dd, J = 10.92, 2.51 Hz, 1H), 7.79 (s, 1H), 7.77-7.81 (m, 1H), 8 51 (s, 1H). LCMS (ESI) mass / charge: 370 (M + 1).

Example 58

3- (1- (4,4-Difluorocyclohexyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 5. ¹ H-NMR (400 MHz, DMSO-d ₄ ) δ ppm 1.22 (s, 3H), 1.33-1.49 (m, 1H), 1, 70 (br.s., 6H), 1.92-2.12 (m, 1H), 2.31-2.38 (m, 1H), 2.59-2.64 (m, 1H), 7 40-7.62 (m, 2H); 7.74 (s, 1H). LCMS (ESI) mass / charge: 434 (M + 1).

Example 59

6-Fluoro-3- (4-methyl-1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 carboxamide

This example was obtained according to the method described in example 5. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.05 (t, J = 7.22 Hz, 1H), 1.36 (s, 3H), 1, 50-1.60 (m, 1H), 1.82 (d, J = 11.92 Hz, 3H), 2.21-2.27 (m, 1H), 2.44-2.56 (m, 1H), 2.79 (br.s., 2H), 3.35-3.42 (m, 1H), 3.90-4.05 (m, 1H), 7.32-7.38 (m , 1H); 7.71 (s, 1H). LCMS (ESI) mass / charge: 400 (M + 1).

Example 60

6-Fluoro-3- (1- (2-fluoroethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.45 (s, 3H), 2.01-2.05 (m, 2H), 2.24- 2.47 (m, 2H), 3.05 (m, 2H), 3.24-3.25 (m, 1H), 3.26-3.27 (m, 1H), 3.33-3, 34 (m, 1H), 4.70-4.72 (m, 1H), 4.82-4.93 (m, 1H), 7.37-7.39 (m, 1H), 7.68- 7.79 (d, 1H); 7.81 (s, 1H); 8.45 (br.s., 1H). LCMS (ESI) mass / charge: 362 (M + 1).

Example 61

6-Fluoro-3- (4-methyl-1- (2,2,2-trifluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.37 (s, 3H), 1.79-1.91 (m, 2H), 2.16- 2.27 (m, 2H), 2.58-2.69 (m, 2H), 2.79-2.89 (m, 2H), 2.98-3.10 (m, 2H), 7, 33-7.39 (m, 1H); 7.66-7.75 (m, 2H). LCMS (ESI) mass / charge: 398 (M + 1).

Example 62

6-Fluoro-3- (4-methyl-1- (3,3,3-trifluoropropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.42 (s, 3H), 1.92-2.05 (m, 2H), 2.38 (d , J = 14.93 Hz, 2H), 2.54-2.71 (m, 2H), 2.86 (d, J = 9.79 Hz, 2H), 2.93-3.07 (m, 2H), 3.14 (d, J = 11.17 Hz, 2H), 7.37 (dd, J = 8.16, 2.51 Hz, 1H), 7.70 (dd, J = 10.92 2.51 Hz, 1H); 7.76 (s, 1H); 8.37 (br.s., 1H). LCMS (ESI) mass / charge: 412 (M + 1).

Example 63

3- (1 - ((1-Cyanocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ,) ppm 1.05 (d, J = 2.26 Hz, 2H), 1.32-1.38 (m , 2H), 1.40 (s, 3H), 1.89-2.05 (m, 2H), 2.33 (d, J = 15.69 Hz, 2H), 2.69 (s, 4H) 3.02 (br.s., 2H), 7.38 (dd, J = 8.09, 2.57 Hz, 1H), 7.68-7.83 (m, 2H), 8.28 ( br.s., 1H). LCMS (ESI) mass / charge: 395 (M + 1).

Example 64

3- (1 - ((1-Cyanocyclobutyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.38 (s, 3H), 1.85-1.94 (m, 2H), 2.00-2 09 (m, 1H), 2.18-2.31 (m, 5 N), 2.42-2.52 (m, 2H), 2.63 (t, J = 9.22 Hz, 2H) 2.81 (s, 2H), 2.88 (d, J = 5.65 Hz, 2H), 7.36 (dd, J = 8.03, 2.26 Hz, 1H), 7.69 ( d, J = 2.26 Hz, 1H), 7.73 (s, 1H), 8.30 (br.s., 1H). LCMS (ESI) mass / charge: 409 (M + 1).

Example 65

6-Fluoro-3- (4-methyl-1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.40 (s, 3H), 1.87-1.98 (m, 2H), 2.28- 2.38 (m, 2H), 2.63-2.80 (m, 2H), 2.95-3.05 (m, 2H), 3.07 (s, 3H), 3.07-3, 14 (m, 2H), 3.38-3.47 (m, 2H), 7.33-7.40 (m, 1H), 7.66-7.73 (m, 1H), 7.73- 7.77 (m, 1H); 8.20-8.37 (m, 1H). LCMS (ESI) mass / charge: 422 (M + 1).

Example 66

6-Fluoro-3- (4-methyl-1 - ((tetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.25-1.33 (m, 2H), 1.37 (s, 3H), 1.70 (d , J = 13.30 Hz, 2H), 1.80-1.89 (m, 3H), 2.22 (br.s., 2H), 2.23 (br.s., 2H), 2, 38 (br.s., 2H), 2.67 (br.s., 2H), 3.40-3.47 (m, 2H), 3.94 (dd, J = 11.67, 2.89 Hz, 2H), 7.36 (dd, J = 8.16, 2.51 Hz, 1H), 7.69 (d, J = 2.51 Hz, 1H), 7.72 (br.s., 1H). LCMS (ESI) mass / charge: 414 (M + 1).

Example 67

3- (1 - ((1-Aminocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.72-0.82 (m, 2H), 0.93-1.00 (m, 2H), 1.40 (s, 3H), 1.91-2.03 (m, 2H), 2.26-2.37 (m, 2H), 2.66 (s, 4H), 2.94-3, 06 (m, 2H), 7.33-7.41 (m, 1H), 7.67-7.73 (m, 1H), 7.73-7.77 (m, 1H), 8.22- 8.48 (m, 2H). LCMS (ESI) mass / charge: 385 (M + 1).

Example 68

6-Fluoro-3- (4-methyl-1- (oxetan-3-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 3. ¹ H NMR (400 MHz, chloroform-d) ppm 1,36 (s, 3H), 1,78-1,88 (m, 2H), 2,17-2 25 (m, 2H), 2.36 (br.s., 2H), 2.57-2.68 (m, 2H), 2.72 (d, J = 7.03 Hz, 2H), 4 38-4.47 (m, 2H), 4.60-4.63 (m, 1H), 4.80-4.82 (m, 2H), 7.33-7.39 (m, 1H) 7.68-7.76 (m, 2H). LCMS (ESI) mass / charge: 386 (M + 1).

Example 69

6-Fluoro-3- (1- (2-methoxyethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.45 (s, 3H), 2.07 (ddd, J = 14.68, 10.85, 3, 58 Hz, 2H), 2.46 (d, J = 14.81 Hz, 2H), 3.12 (br.s., 2H), 3.23 (t, J = 4.83 Hz, 2H), 3.41 (s, 5H), 3.66-3.73 (m, 2H), 7.39 (dd, J = 8.16, 2.51 Hz, 1H), 7.71 (dd, J = 10.92, 2.51 Hz, 1H), 7.80 (s, 1H), 8.52 (s, 1H). LCMS (ESI) mass / charge: 374 (M + 1).

Example 70

6-Fluoro-3- (1 - ((1-hydroxycyclopropyl) methyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.64-0.74 (m, 2H), 0.84-0.93 '(m, 2H) 1.46 (s, 3H), 2.04-2.18 (m, 2H), 2.50 (d, J = 15.18 Hz, 2H), 3.16 (br.s., 4H) 3.47-3.68 (m, 2H), 7.36-7.43 (m, 1H), 7.68-7.75 (m, 1H), 7.79-7.84 (m, 1H), 8.48-8.65 (m, 1H). LCMS (ESI) mass / charge: 386 (M + 1).

Example 71

6-Fluoro-3- (4-methyl-1 - ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol- 8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.38 (s, 3H), 1.46 (s, 3H), 1.81-1.93 ( m, 2H), 2.18-2.29 (m, 2H), 2.33-2.54 (m, 2H), 2.54-2.84 (m, 4H), 4.31-4, 35 (m, 2H), 4.49-4.54 (m, 2H), 7.34-7.39 (m, 1H), 7.68-7.75 (m, 2H). LCMS (ESI) mass / charge: 400 (M + 1).

Example 72

6-Fluoro-3- (1- (3-methoxypropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.45 (s, 3H), 1.94-2.01 (m, 2H), 2.02-2 12 (m, 2H), 2.47 (d, J = 13.05 Hz, 2H), 2.89-3.20 (m, 4H), 3.34 (s, 3H), 3.39 ( br.s., 2H), 3.45-3.52 (m, 2H), 7.38 (dd, J = 8.09, 2.57 Hz, 1H), 7.71 (dd, J = 10 92, 2.51 Hz, 1H), 7.79 (s, 1H), 8.55 (s, 1H). LCMS (ESI) mass / charge: 434 (M + 1).

Example 73

6-Fluoro-3- (4-methyl-1 - ((1- (methylsulfonyl) cyclopropyl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 0.95-1.01 (w, 2H), 1.38 (s, 3H), 1.41-1 49 (m, 2H), 1.83-1.96 (m, 2H), 2.27 (d, J = 13.30 Hz, 2H), 2.55 (br.s., 2H), 2 86 (s, 2H), 2.92 (br.s., 2H), 3.24 (s, 3H), 7.36 (dd, J = 8.16, 2.51 Hz, 1H), 7 67-7.78 (m, 2H). LCMS (ESI) mass / charge: 448 (M + 1).

Example 74

6-Fluoro-3- (4-methyl-1- (thiazol-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.36-1.42 (m, 3H), 1.86-1.97 (m, 2H), 2.23-2.33 (m, 2H), 2.63-2.73 (m, 2H), 2.89-2.98 (m, 2H), 4.02-4.07 (m, 2H) ), 7.32-7.40 (m, 1H), 7.58-7.63 (m, 1H), 7.68-7.73 (m, 1H), 7.74 (s, 1H), 7.75-7.79 (m, 1H); 8.25-8.35 (m, 1H). LCMS (ESI) mass / charge: 413 (M + 1).

Example 75

6-Fluoro-3- (4-methyl-1- (methylsulfonyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H-NMR (MeOD, 400 MHz) δ: 1.38-1.46 (m, 3H), 1.88 (ddd, J = 13.68, 9, 66, 3.76 Hz, 2H), 2.32 (d, J = 15.06 Hz, 2H), 2.78 (s, 3H), 3.00-3.17 (m, 2H), 3, 46-3.53 (m, 2H), 7.35-7.41 (m, 1H), 7.69-7.75 (m, 1H), 7.77-7.79 (m, 1H), 8.46-8.53 (m, 1H). LCMS (ESI) mass / charge: 394 (M + 1).

Example 76

6-Fluoro-3- (1- (3-fluorocyclobutyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.45 (s, 3H), 1.96-2.18 (m, 2H), 2, 38-2.74 (m, 6H), 2.94 (br.s., 4H), 3.74-3.93 (m, 1H), 5.12-5.32 (m, 1H), 7 41 (dd, J = 8.16, 2.38 Hz, 1H), 7.67 (dd, J = 10.79, 2.26 Hz, 1H), 7.79 (s, 1H), 8, 52 (br.s., 1H). LCMS (ESI) mass / charge: 388 (M + 1).

Example 77

6-Fluoro-3- (4-methyl-1- (thiophen-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.34 (s, 3H), 1.82 (ddd, J = 13.36, 9.41, 3, 45 Hz, 2H), 2.13-2.27 (m, 1H), 2.32-2.53 (m, 1H), 2.69 (br.s., 2H), 3.72 (s, 2H), 6.87-7.01 (m, 2H), 7.25-7.39 (m, 2H), 7.62-7.75 (m, 2H). LCMS (ESI) mass / charge: 412 (M + 1).

Example 78

3- (1 - ((1-Ethylpiperidin-4-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (400 MHz, methanol-d4) δ ppm 1.32-1.35 (t, 3H), 1.42 (s, 3H), 1.47 -1.51 (d, 2H), 1.99-2.08 (m, 5H), 2.35-2.38 (d, 2H), 2.64-2.65 (d, 2H), 2.89 (m, 2H), 3.06 (t, 2H), 3.11-3.15 (m, 4H), 3.51-3.54 (d, 2H), 7.37-7, 39 (m, 1H), 7.70-7.74 (m, 1H), 7.77 (s, 1H), 8.446 (s, 2H). LCMS (ESI) mass / charge: 441 (M + 1).

Example 79

6-Fluoro-3- (4-methyl-1 - ((1-methylazetidin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.32 (s, 3H), 1.89-1.95 (m, 2H), 2, 29-2.33 (d, 2H), 2.60 (d, 2H), 2.86-2.91, 2.64-2.65 (m, 7H), 3.18 (m, 1H) 3.84-3.88 (t, 2H), 4.15-4.20 (t, 2H), 7.36-7.39 (m, 1H), 7.70-7.73 (m, 1H), 7.77 (s, 1H), 8.41 (s, 2H). LCMS (ESI) mass / charge: 399 (M + 1).

Example 80

Ethyl 2 - ((4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-yl) methyl) cyclopropanecarboxylate

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) 0.86-1.34 (m, 6 N), 1.35-1.49 (m, 2H), 1.57-2.01 (m, 4H), 2.09-2.28 (m, 2H), 2.44-2.70 (m, 2H), 2.99-3.27 (m, 2H) ), 3.36-3.47 (m, 2H), 3.53-3.75 (m, 2H), 4.06-4.26 (m, 3H), 7.50-7.65 (m , 1H); 7.74-7.85 (m, 1H); 8.05 (br.s., 1H). LCMS (ESI) mass / charge: 442 (M + 1).

Example 81

Ethyl 3- (1 - ((2- (dimethylcarbamoyl) cyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) 0.97-1.29 (m, 2H), 1.47 (s, 2H), 1.65 (s , 1H), 2.08-2.30 (m, 3H), 2.63 (d, J = 15.3 Hz, 1H), 2.85 (s, 1H), 2.92-3.01 ( m, 3H), 3.01-3.12 (m, 2H), 3.12-3.27 (m, 2H), 3.29 (s, 2H), 3.34-3.47 (m, 2H), 3.55-3.77 (m, 2H), 7.56-7.70 (m, 1H), 7.78-7.85 (m, 1H), 8.12 (d, J = 6.5 Hz, 1H). LCMS (ESI) mass / charge: 441 (M + 1).

Example 82

6-Fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H-NMR (MeOD, 400 MHz) δ: 1.00-1.02 (d, 6H), 1.43 (s, 3H), 2.03-2 07 (m, 3H), 2.10-2.11 (d, 2H), 2.81-2.83 (d, 2H), 3.03 (bs, 2H), 3.31 (bs, 2H) ), 7.35-7.38 (dd, 1H), 7.67-7.71 (s, 1H), 7.77 (s, 1H), 8.53 (bs, 1H). LCMS (ESI) mass / charge: 372 (M + 1).

Example 83

6-Fluoro-3- (4-methyl-1 - ((4-methylthiazol-5-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol- 8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 1.41 (s, 3H), 1.89-2.01 (m, 2H), 2.30 -2.39 (m, 2H), 2.43 (s, 3H), 2.73-2.86 (m, 2H), 2.97-3.15 (m, 2H), 4.01-4 20 (m, 2H), 7.30-7.47 (m, 1H), 7.65-7.86 (m, 2H), 8.90-9.04 (m, 1H). LCMS (ESI) mass / charge: 427 (M + 1).

Example 84

6-Fluoro-3- (4-methyl-1 - ((1-methyl-1H-imidazol-2-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2- b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, methanol-d ₄ ,) ppm 1.32-1.44 (m, 3H), 1.78-1.96 (m, 2H) 2.18-2.33 (m, 2H), 2.46-2.62 (m, 2H), 2.71-2.88 (m, 2H), 3.73-3.77 (m, 2H), 3.81 (s, 3H), 7.01-7.11 (m, 1H), 7.18-7.23 (m, 1H), 7.33-7.40 (m, 1H) 7.73 (s, 2H); 8.28-8.44 (m, 1H). LCMS (ESI) mass / charge: 410 (M + 1).

Example 85

3- (1 - ((1,2-Dimethyl-1H-imidazol-5-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2 -b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 2. ¹ H NMR (400 MHz, methanol-d ₄₎ ppm 1,38 (s, 3H), 1,83-1,92 (m, 2H), 2.27 ( d, J = 13.80 Hz, 2H), 2.54 (s, 5 N), 2.86 (d, J = 10.92 Hz, 2H), 3.70 (s, 2H), 3.75 (s, 3H), 7.17 (s, 1H), 7.36 (dd, J = 8.16, 2.51 Hz, 1H), 7.66-7.80 (m, 2H), 8, 38 (br.s., 1H). LCMS (ESI) mass / charge: 424 (M + 1).

Example 86

3- (1'-Ethyl-4-methyl- [1,4'-bipiperidin] -4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8- carboxamide

This example was prepared according to the method described in Example 2. ¹ H-NMR (400 MHz, methanol-d ₄₎ 1,09 (t, J = 7,09 Hz, 3H), 1,27 (s, 3H), 1 50-1.70 (m, 2H), 1.72-1.85 (m, 2H), 1.92 (d, J = 11.54 Hz, 2H), 2.34 (br.s., 2H), 2.75 (d, J = 7.40 Hz, 7 H), 2.86 (br.s., 2H), 3.23 (d, J = 10.42 Hz, 2H), 7, 49 (d, J = 8.41 Hz, 1H), 7.58 (dd, J = 10.85, 2.20 Hz, 1H), 7.79 (s, 1H), 8.28 (s, 2H ) LCMS (ESI) mass / charge: 427 (M + 1).

Example 87

6-Fluoro-3- (4-methyl-1 - ((6-oxo-1,6-dihydropyridazin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1, 2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 2. ¹ H NMR (400 MHz, MeOD) δ: 8.35 (s, 1H), 7.70-7.74 (m, 2H), 7.57-7, 60 (d, 1H), 7.36-7.38 (t, 1H), 6.98-7.00 (d, 1H), 3.63 (s, 2H), 2.86 (m, 2H) 2.61-2.63 (m, 2H); 2.26-2.30 (d, 2H); 1.87-1.94 (m, 2H); 1.39 (s, 3H). LCMS (ESI) mass / charge: 424 (M + 1).

Example 88

3- (1- (2-Cyanoethyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 53D (52 mg, 0.125 mmol), acrylonitrile (66 mg, 1.25 mmol) and potassium carbonate (172 mg, 1.25 mmol) in DMF (18 ml) was stirred at 28 ° C. for 1 hour. After completion, the reaction mixture was quenched with water (10 ml). The aqueous layer was extracted with EtOAc (20 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (31 mg, 66.0% yield). ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.39 (s, 3H), 1.86-1.97 (m, 2H), 2.25-2.36 (m, 2H), 2, 60-2.70 (m, 2H), 2.74 (s, 2H), 2.84-2.98 (m, 4H), 7.33-7.41 (m, 1H), 7.68- 7.73 (m, 1H), 7.74 (s, 1H), 8.21-8.32 (m, 1H). LCMS (ESI) mass / charge: 369 (M + 1).

Example 89

6-Chloro-3- (1-ethyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 53, replacing (2,6-dibromo-4-chlorophenyl) hydrazine with (2,6-dibromo-4-fluorophenyl) hydrazine. ¹ H-NMR (MeOD, 400 MHz) δ: 1.32-1.39 (t, 3H), 1.46 (m, 1H), 2.52-2.55 (s, 3H), 2.06 -2.08 (m, 2H), 2.47-2.48 (m, 2H), 3.09-3.11 (m, 3H), 3.34-3.41 (m, 3H), 7 63 (s, 1H); 7.83 (s, 1H); 7.97-7.97 (d, 1H); 8.54 (bs, 1H). LCMS (ESI) mass / charge: 360 (M + 1).

Example 90

3- (1-Ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 53, replacing tert-butyl-3- (hydroxymethyl) -3-methylpyrrolidine-1-carboxylate with tert-butyl-4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.38 (s, 3H), 1.64 (s, 3H), 2.25-2.42 (m, 1H), 2.59-2, 76 (m, 1H), 3.27-3.32 (m, 2H), 3.39-3.53 (m, 1H), 3.54-3.71 (m, 2H), 3.71- 3.88 (m, 1H), 7.33-7.39 (m, 1H), 7.57-7.70 (m, 1H), 7.76-7.90 (m, 1H), 8, 28-8.80 (m, 1H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 91

3- (1,3-dimethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 90. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 8.52 (br.s., 1H), 7.84 (s, 1H), 7.67 (dd, J = 2.5, 10.9 Hz, 1H), 7.38 (dd, J = 2.5, 8.0 Hz, 1H), 3.74 (d, J = 11.3 Hz, 1H), 3.67-3.49 (m, 2H), 3.40 (d, J = 11.3 Hz, 1H), 2.96 (s, 3H), 2.73-2.60 (m , 1H), 2.34 (td, J = 7.8, 13.4 Hz, 1H), 1.64 (s, 3H). LCMS (ESI) mass / charge: 316 (M + 1).

Example 92

6-Fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 90. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.38-1.52 (m, 6H), 1.71 (d, J = 2.26 Hz, 3H), 2.32-2.46 (m, 1H), 2.63-2.82 (m, 1H), 3.38-3.70 (m, 3H), 3.76-4.11 ( m, 2H), 7.58-7.70 (m, 1H), 7.76-7.86 (m, 1H), 8.15-8.29 (m, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 93

3- (1- (Cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 5. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.41-0.52 (m, 2H), 0.70-0.82 (m, 2H), 1.10-1.26 (m, 1H), 1.66 (s, 3H), 2.27-2.39 (m, 1H), 2.63-2.75 (m, 1H), 3, 17 (d, J = 7.15 Hz, 2H), 3.44-3.58 (m, 1H), 3.59-3.78 (m, 2H), 3.79-3.94 (m, 1H), 7.27-7.40 (m, 1H), 7.55-7.67 (m, 1H), 7.77-7.89 (m, 1H), 8.43-8.69 ( m, 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 94

6-Fluoro-3- (3-methyl-1- (oxetan-3-yl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 5. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.58 (s, 3H), 2.01-2.10 (m, 1H), 2.26- 2.35 (m, 1H), 2.68-2.74 (m, 1H), 2.79-2.87 (m, 1H), 2.87-2.96 (m, 1H), 2, 96-3.03 (m, 1H), 3.78-3.85 (m, 1H), 4.62-4.72 (m, 1H), 4.74-4.81 (m, 1H), 7.31-7.40 (m, 1H); 7.64-7.71 (m, 1H); 7.72-7.77 (m, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 95

6-Fluoro-3- (1- (2-fluoroethyl) -3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H-NMR (MeOD, 400 MHz) δ: 1.635 (s, 1H), 2.243-2.263 (m, 1H), 2.522-2.554 (m, 1H), 3.288- 3.321 (d, 1H), 3.325 (s, 2H), 3.329-3.337 (m, 1H), 3.391-3.414 (m, 1H), 3.632-3.659 (d, 1H), 4.730-4.860 (dt, 2H), 7.291-7.317 (dd, 1H), 7.586-7.619 (dd, 1H), 7.788 (s, 1H), 8.445 (bs, 1H), LCMS (ESI) mass / charge: 348 (M + 1).

Example 96

3- (1 - ((2,2-Difluorocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.34-1.46 (m, 1H) 1.64 (s, 3H) 1.67-1, 79 (m, 1H) 2.03-2.11 (m, 1H) 2.20-2.31 (m, 1H) 2.52-2.63 (m, 1H) 3.13-3.24 ( m, 1H) 3.24-3.31 (m, 2H) 3.37-3.48 (m, 1H) 3.48-3.58 (m, 1H) 3.59-3.67 (m, 1H) 7.29-7.39 (m, 1H) 7.57-7.67 (m, 1H) 7.76-7.84 (m, 1H) 8.35-8.54 (m, 1H) . LCMS (ESI) mass / charge: 392 (M + 1).

Example 97

6-Fluoro-3- (3-methyl-1- (2,2,2-trifluoroethyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.74 (s, 3H), 2.39-2.54 (m, 1H), 2.74- 2.88 (m, 1H), 3.69-3.82 (m, 1H), 3.82-3.95 (m, 2H), 3.97-4.14 (m, 1H), 4, 36-4.50 (m, 2H), 7.55-7.64 (m, 1H), 7.73-7.83 (m, 1H), 8.12-8.20 (m, 1H). LCMS (ESI) mass / charge: 384 (M + 1).

Example 98

6-Fluoro-3- (3-methyl-1- (2- (methylsulfonyl) ethyl) pyrrolidin-3-yl) -4H-benzo] [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.60 (s, 3H), 2.05-2.15 (m, 1H), 2.18- 2.28 (m, 1H), 2.63-2.69 (m, 1H), 2.69-2.78 (m, 1H), 3.01-3.10 (m, 1H), 3, 11 (s, 3H), 3.26-3.31 (m, 1H), 3.34-3.41 (m, 2H), 3.41-3.50 (m, 1H), 3.50- 3.60 (m, 1H), 7.35-7.45 (m, 1H), 7.63-7.70 (m, 1H), 7.72 (s, 1H), 8.22 (s, 1H). LCMS (ESI) mass / charge: 408 (M + 1).

Example 99

6-Fluoro-3- (3-methyl-1- (3,3,3-trifluoropropyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ,) ppm 1.62 (s, 3H), 2.16-2.25 (m, 1H), 2.43 -2.53 (m, 1H), 2.58-2.72 (m, 1H), 3.08-3.14 (m, 1H), 3.16-3.29 (m, 1H), 3 , 34-3.39 (m, 1H), 3.41-3.47 (m, 1H), 7.32-7.41 (m, 1H), 7.63-7.71 (m, 1H) 7.74-7.83 (m, 1H); 8.24-8.34 (m, 1H). LCMS (ESI) mass / charge: 398 (M + 1).

Example 100

3- (1 - ((1-Aminocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 0.85 (s, 1H), 1.00 (s, 1H), 1.62 (s, 3H) , 2.07-2.17 (m, 1H), 2.34-2.44 (m, 1H), 2.85 (s, 1H), 2.94-3.01 (m, 1H), 3 04-3.12 (m, 1H), 3.20 (d, J = 9.41 Hz, 1H), 7.33-7.39 (m, 1H), 7.64-7.70 (m , 1H), 7.75-7.80 (m, 1H), 7.83-7.85 (m, 1H), 8.02-8.05 (m, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) mass / charge: 371 (M + 1).

Example 101

3- (1 - ((1-Cyanocyclobutyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 3. ¹ H NMR (400 MHz, methanol-d ₄ ) 1.60 (s, 3H), 2.00-2.11 (m, 2H), 2.13-2 23 (m, 1H), 2.25-2.40 (m, 3H), 2.45-2.58 (m, 2H), 2.65-2.70 (m, 1H), 2.72 2.80 (m, 1H), 2.93 (s, 1H), 2.99-3.06 (m, 1H), 3.14-3.23 (m, 2H), 7.38-7 44 (m, 1H), 7.69 (dd, J = 10.85, 2.57 Hz, 1H), 7.74 (s, 1H), 8.33 (br.s., 1H). LCMS (ESI) mass / charge: 395 (M + 1).

Example 102

3- (1 - ((1-Cyanocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was prepared according to the method described in Example 3. ¹ H NMR (400 MHz, DMSO-d ₆₎ ppm 0,92 (d, J = 2,26 Hz, 2H), 1,16-1,24 (m, 2H), 1.48 (s, 3H), 1.87-1.97 (m, 1H), 2.05 (s, 1H), 2.55 (d, J = 7.53 Hz, 4H), 2.91 (s, 2H), 7.43-7.50 (m, 1H), 7.51-7.61 (m, 1H), 7.79 (s, 1H). LCMS (ESI) mass / charge: 381 (M + 1).

Example 103

3- (1- (2-Cyanoethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 88. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 1.61 (s, 3H), 2.06-2.16 (m, 1H), 2.23- 2.33 (m, 1H), 2.80 (d, J = 6.40 Hz, 1H), 2.83-2.91 (m, 1H), 2.93-3.02 (m, 1H) , 3.03-3.12 (m, 1H), 3.27 (d, J = 9.29 Hz, 2H), 7.37-7.44 (m, 1H), 7.64-7.72 (m, 1H); 7.76 (s, 1H); 8.14-8.26 (m, 1H). LCMS (ESI) mass / charge: 355 (M + 1).

Example 104

3- (1- (Cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 93. ¹ H NMR (400 MHz, MeOD) δ: 8.51 (s, 1H), 7.96 (s, 1H), 7.70-7.73 (dd, 1H), 7.39-7.41 (dd, 1H), 4.39-4.32 (d, 2H), 4.23-4.26 (d, 2H), 3.15-3.17 ( d, 2H), 1.87 (s, 3H), 1.06-1.08 (m, 1H), 0.69-0.74 (m, 2H), 0.42-0.46 (m, 2H). LCMS (ESI) mass / charge: 342 (M + 1).

Scheme D

Example 105

6-Fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 105A

tert-Butyl 4- (1-cyano-2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate

A mixture of tert-butyl 4-oxopiperidin-1-carboxylate (100 g, 0.5 mol), ethyl 2-cyanoacetate (56.5 g, 0.5 mol), NH ₄ OAc (19.2 g, 0, 25 mol) and HOAc (15 g, 0.25 mol) in toluene (1 L) were stirred at 120 ° C for 5-6 hours to remove water using a Dean-Stark nozzle. After removing the solvent under vacuum, the residue was partitioned between EtOAc (500 ml) and water (500 ml), the aqueous layer was extracted with EtOAc (500 ml × 3). The combined organic layers were washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by trituration with PE / EtOAc = 10/1 (300 ml). A white solid was collected by filtration to give the title compound (90 g, 61% yield). ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.38 (t, J = 7.15 Hz, 3H), 1.50 (s, 9H), 2.79 (t, J = 5.90 Hz , 2H), 3.15 (t, J-5.83 Hz, 2H), 3.56 (t, J = 5.71 Hz, 2H), 3.63 (t, J = 5.83 Hz, 2H ), 4.31 (q, J = 7.15 Hz, 2H). LCMS (ESI) mass / charge: 295 (M + 1).

Example 105B

tert-Butyl 4- (1-cyano-2-ethoxy-2-oxoethyl) -4-methylpiperidine-1-carboxylate

To a mixture of CuI (86.3 g, 0.454 mol) in dry THF (1.7 L) was added dropwise 3 M methylmagnesium bromide (378 ml, 1.13 mol) at -60-70 ° C under N ₂ . After stirring at -10 ° C-0 ° C for 1 h and cooling to -60-70 ° C, a solution of Example 105A (133.5 g, 0.454 mol) in THF (300 ml) was added. The mixture was stirred at 20 ° C for 15 hours, and then cooled to 0 ° C and quenched with sat. aq. NH ₄ Cl solution (1.2 L). After filtration through a pad of celite, the aqueous layer was extracted with EtOAc (600 ml × 3). The combined organic layers were washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound (142 g) as a yellow oil, which was used directly in the next step without further purification.

Example 105C

2- (1- (tert-butoxycarbonyl) -4-methylpiperidin-4-yl) -2-cyanoacetic acid

To a solution of Example 105B (142 g, crude, 0.458 mol) in a mixture of THF / MeOH = 10: 1 (1.2 L) was added dropwise a solution of NaOH (73.3 g, 1.82 mol) in water (320 ml) at 0 ° C. After completion of the dropwise addition, the mixture was stirred at 20 ° C for 2 hours, and then diluted by adding water (320 ml). The aqueous layer was extracted with EtOAc (500 ml × 3). The combined organic layers were washed with water (200 ml × 2). The combined aqueous layer was adjusted to pH 3-4 with 1N. HCl and was extracted with DCM / MeOH = 10: 1 (300 ml × 6). The combined organic layer of DCM / MeOH was washed with brine (800 ml) and then dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound (111.5 g) as a yellow solid, which was used directly in the next step without additional cleaning.

Example 105D

tert-Butyl 4- (cyanomethyl) -4-methylpiperidin-1-carboxylate

A mixture of Example 105C (111.5 g, crude, 0.395 mol) and Cu ₂ O (11.4 g, 79.08 mmol) in acetonitrile (900 ml) was stirred at 80 ° C for 2 hours.

After cooling to room temperature, the mixture was evaporated, and the residue was dissolved in EtOAc (1 L) and filtered through a pad of celite to remove insoluble matter. The filter residue was washed with EtOAc (250 ml × 2). THF (150 ml) was added to the filtrate to dissolve the precipitates. The organic layer was washed with water, with a mixture of water / brine = 1: 1 (300 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by trituration with PE / EtOAc = 10/1 (300 ml). A white solid was collected by filtration to give the title compound (98 g). LCMS (ESI) mass / charge: 239 (M + 1).

Example 105E

tert-butyl-4- (1-cyano-2-oxoethyl) -4-methylpiperidine-1-carboxylate

To a mixture of Example 105D (50 g, 0.21 mol) in THF (400 mL) was added dropwise 2M LDA (160 mL, 0.32 mol) at - 60-70 ° C under N _2. After stirring at - 60-70 ° C for 1 h, ethyl formate (32 g, 0.43 mol) was added dropwise until completion, followed by slow heating to 15 ° C and stirring for another 4 hours. The completion field was quenched aq. NH ₄ Cl solution (500 ml). The aqueous layer was extracted with EtOAc (200 ml × 3). The combined organic layers were washed with water (200 ml), 1H. HCl (300 ml × 3), brine (200 ml), then dried over Na ₂ SO ₄ , filtered and evaporated to give a residue, which was purified by trituration with PE / EtOAc = 10/1 (200 ml). A white solid was collected by filtration to give the title compound (45 g, 80% yield). LCMS (ESI) mass / charge: 267 (M + 1).

Example 105F

(2,6-Dibromo-4-fluorophenyl) hydrazine hydrochloride

To a mixture of 2,6-dibromo-4-fluoroaniline (50 g, 0.186 mol) c. conc. HCl (190 ml) was added dropwise a solution of NaNO ₂ (14.1 g, 0.205 mol) in water (70 ml) at -5-0 ° C. After stirring at -5-0 ° C for 40 minutes, the above reaction mixture was added dropwise to a solution of SnCl ₂ -2H ₂ O (62.95 g, 0.279 mol) in conc. HCl (240 ml) at -5-0 ° C. The resulting mixture was slowly heated to 20 ° C and stirred for 12 hours. The solid was collected by filtration, washed with iso-PrOH (200 ml) and then dried under vacuum to give the title compound (47 g, 78% yield) ), which could be used directly in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆₎ δ ppm 2,37-2,68 (m, 1H ), 6,94-7,28 (m, 1H), 7,80 (d, J = 8, 03 Hz, 2H), 10.13 (br.s., 3H).

Example 105G

tert-Butyl 4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazol-4-yl) -4-methylpiperidin-1-carboxylate

A mixture of example 105E (50 g, 187.73 mmol), KOAc (27.64 g, 281.73 mmol) and example 105F (72.17 g, 225.28 mmol) in ethanol (500 ml) was stirred at 60 ° C. within 5 hours. After completion of the reaction, NaHCO ₃ (31.57 g, 375.78 mmol) was added to the mixture with stirring at 80 ° C for another 15 hours. After cooling to room temperature, the resulting mixture was evaporated and the residue was dissolved with using EtOAc (200 ml) and water (200 ml). The aqueous layer was extracted with EtOAc (200 ml × 3). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by trituration with PE / EtOAc = 10/1 (200 ml). A white solid was collected by filtration to give the title compound (75 g, 75% yield), which could be used directly in the next step without further purification.

Example 105H

tert-Butyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

A mixture of example 105G (35 g, 65.78 mmol), Pd ₂ (dba) ₃ (6.02, 6.57 mmol), xanthos (7.61 g, 13.16 mmol) and Cs ₂ CO ₃ (42, 77 g, 131.58 mmol) in DMF (300 ml) was stirred at 130 ° C. for 9 hours under N ₂ . After cooling to room temperature, the resulting mixture was filtered and the filtrate was evaporated. The residue was dissolved in EtOAc (500 ml). The organic layer was washed with water (200 ml × 2), brine (200 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated to give the crude title compound as a brown oil, which could be used in the next step without further purification . LCMS (ESI) mass / charge: 451, 453 (M, M + 2).

Example 105I

tert-Butyl-4- (8-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidine-1-carboxylate

The mixture of example 105H (29.7 g, crude, 65.8 mmol), Zn (CN) ₂ (15.4 g, 131.71 mmol), Pd ₂ (dba) ₃ (6.02 g, 6.58 mmol ), DPPF (7.30 g, 13.17 mmol) and Zn (8.65 g, 131.71 mmol) in DMF (300 ml) were stirred at 120 ° C for 5 h in an atmosphere of N ₂ . After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to give a residue, which was purified by column chromatography to obtain the crude title compound (35 g, crude) as a yellow foam. LCMS (ESI) mass / charge: 398 (M + 1).

Example 105J

tert-Butyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

To the solution of Example 105I (35 g, crude, 88.17 mmol) and 1H. NaOH (140 ml, 140 mmol) in DMSO (100 ml) was added dropwise 30% H ₂ O ₂ (40 ml) at 0 ° C. After completion of the dropwise addition, the reaction solution was heated to 40-50 ° C and stirred for 2 hours, and then diluted with water (200 ml) and extracted with EtOAc / THF = 3/1 (200 ml × 2). The combined organic layers were washed with water (150 ml × 2), brine (150 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (12.2 g, yield: 45%) as yellow solids. LCMS (ESI) mass / charge: 416 (M + 1).

Example 105K

6-Fluoro-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A solution of Example 105J (5 g, 12 mmol) in a DCM / TFA mixture (50 ml / 10 ml) was stirred at 20 ° C. for 2 hours. The resulting mixture was evaporated to give the title compound as a yellow oil, which could be used. in the next step without further purification.

Example 105L

6-Fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A solution of Example 105K (3.8 g, crude, 12 mmol), Na (CN) BH ₃ (2.8 g, 60 mmol) in a mixture of acetone (2.0 g, 34 mmol) and methanol (50 ml) was stirred at 25 ° C. for 3 hours. After removal of the solution under vacuum, the residue was dissolved in EtOAc / THF = 5/1 (200 ml). The organic layers were washed with water (50 ml × 2), brine (50 ml), then dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (4 g, yield: 90%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.11-1.61 (m, 9 H), 1.89-2.29 (m, 2H), 2.47 (br.s. , 1H), 2.55 (br.s., 1H), 2.77 (d, J = 12.05 Hz, 1H), 3.09-3.66 (m, 4H), 7.53 (dd , J = 8.28, 2.51 Hz, 1H), 7.63 (dt, J = 10.92, 2.26 Hz, 1H), 7.79-7.99 (m, 1H), 8, 17 (br.s., 1H), 10.23-10.75 (m, 2H), 12.49-12.93 (m, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 106

6-Fluoro-3- (4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 106A

8-Bromo-6-fluoro-3- (4-methyltetrahydro-2H-thiopyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole

This example was obtained as described in Examples 105A-105H, replacing dihydro-2H-thiopyran-4 (3H) -one with tert-butyl-4-oxopiperidine-1-carboxylate. LCMS (ESI) mass / charge: 368, 370 (M, M + 2).

Example 106B

4- (8-Bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methyltetrahydro-2H-thiopyran-1,1-dioxide

A mixture of Example 106A (0.1 g, 0.271 mmol) and tCPBA (0.94 g, 0.542 mmol) in DCM (15 ml) and THF (3 ml) was stirred at 25 ° C. for 3 hours. The mixture was quenched with sat. aq. Na ₂ SO ₃ solution (20 ml). The aqueous layer was extracted with DCM (15 ml × 3). The combined organic layers were washed with sat. aq. NaHCO ₃ solution (20 ml), brine (15 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound, which could be used directly in the next step without further purification.

Example 106C

6-Fluoro-3- (4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 105I and 105J. ¹ H NMR (400 MHz, MeOD) δ: 7.8798 (s, 1H), 7.56-7.59 (d, 1H), 7.46-7.48 (d, 1H), 3.11 ( m, 2H), 2.95-3.01 (m, 2H), 2.52 (m, 2H), 2.13-2.19 (m, 2H), 1.35 (s, 3H). LCMS (ESI) mass / charge: 365 (M + 1).

Example 107

3- (1,4-Diethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 107A

tert-Butyl-4- (1-cyano-2-ethoxy-2-oxoethyl) -4-ethylpiperidin-1-carboxylate 1,4-ethylpiperidin-4-yl

Ethyl magnesium bromide (2.83 ml, 8.49 mmol) was added dropwise to the mixture of Example 105A (1.0 g, 3.4 mmol) in THF (20 ml) at −78 ° C. under N ₂ . After stirring at -78 ° C for 1 h, the mixture was heated to 32 ° C and stirred for 15 h, and then quenched with sat. aq. NH ₄ Cl solution (100 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (0.8 g, yield: 73%) as a colorless oil. LCMS (ESI) mass / charge: 325 (M + 1).

Example 107B

3- (1,4-Diethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in example 105. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.80 (t, J = 7.47 Hz, 3H), 1.28 (t, J = 7 , 34 Hz, 3H), 1.72 (d, J = 7.40 Hz, 1H), 1.89-2.14 (m, 1H), 2.41-2.61 (m, 1H), 3 06 (d, J = 7.28 Hz, 3H), 3.37-3.58 (m, 1H), 7.35 (dd, J = 8.16, 2.51 Hz, 1H), 7, 69 (dd, J = 10.92, 2.64 Hz, 1H), 7.76 (s, 1H), 8.52 (s, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 108

3- (4-cyano-1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 108A

tert-butyl-4-cyano-4- (cyanomethyl) piperidine-1-carboxylate

A solution of example 105A (2.0 g, 6.8 mmol) and KCN (1.71 g, 26.3 mmol) in a mixture of ethanol (20 ml) / water (4 ml) was stirred at 70-80 ° C for 15 h. After removing the solution under vacuum, the residue was dissolved by adding water (100 ml). The aqueous phase was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (1.3 g, yield: 79%) as a white solid. LCMS (ESI) mass / charge: 250 (M + 1).

Example 108B

tert-Butyl 4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazol-4-yl) -4-cyanopiperidine-1-carboxylate

This example was obtained as described in examples 105E-105G.

Example 108C

tert-Butyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-cyanopiperidine-1-carboxylate

A mixture of example 108B (660 mg, 1.22 mmol), CuI (70 mg, 0.37 mmol), N ¹ , N ² -dimethylethan-1,2-diamine (65 mg, 0.74 mmol) and K ₃ PO ₄ (780 mg, 3.68 mmol) in DMF (15 ml) was stirred at 70 ° C for 10 hours in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered through a pad of celite. The filtrate was evaporated and the residue was purified by column chromatography to give the title compound (470 mg, yield: 78%) as white solids. LCMS (ESI) mass / charge: 462, 464 (M, M + 2).

Example 108D

3- (4-cyanopiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 1G-1J. LCMS (ESI) mass / charge: 327 (M + 1).

Example 108E

3- (4-cyano-1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 5. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.34 (d, J = 5.90 Hz, 2H), 0.67-0.75 ( m, 2H), 0.99-1.13 (m, 1H), 2.37 (br.s., 2H), 2.58 (br.s., 2H), 2.75 (d, J = 6.90 Hz, 2H), 2.89-3.07 (m, 2H), 3.39-3.61 (m, 2H), 7.44 (dd, J = 8.09, 2.57 Hz , 1H), 7.75 (dd, J = 10.85, 2.57 Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) mass / charge: 381 (M + 1).

Example 109

3- (1-Cyclopropylmethyl) -4- (hydroxymethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 109A

4- (8-Bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid

A mixture of Example 108C (800 mg, 1.73 mmol) and 40% aq. a solution of NaOH (5 ml) in ethanol (25 ml) was stirred at 80-90 ° C for 15 hours. After cooling to room temperature, the mixture was acidified to pH 3-4 with 1N. HCl and was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (50 ml × 2), brine (50 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (850 mg, purity: 79%, yield: 98%) in as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) mass / charge: 481, 483 (M, M + 2).

Example 109B

tert-Butyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4- (hydroxymethyl) piperidine-1-carboxylate

To the mixture of Example 109A (800 mg, 1.56 mmol) in THF (15 ml) was added 10 M BH ₃ -DMS (1 ml, 10 mmol) at 0 ° C under N ₂ . After completion of the dropwise addition, the mixture was stirred at 0 ° C for 2 hours, then quenched with MeOH (20 ml) and the solvent was evaporated in vacuo. The residue was purified by column chromatography to give the title compound as white solids. (508 mg, yield: 70%). LCMS (ESI) mass / charge: 467, 469 (M, M + 2).

Example 109C

tert-Butyl-4- (8-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4- (hydroxymethyl) piperidine-1-carboxylate

The mixture of example 109B (450 mg, 0.96 mmol), Zn (CN) ₂ (225 mg, 1.92 mmol), Pd ₂ (dba) ₃ (176 mg, 0.19 mmol), DPPF (215 mg, 0 , 38 mmol) and Zn (125 mg, 1.92 mmol) in DMF (5 ml) was stirred at 120 ° C for 15 h in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound as brown solids (387 mg, yield: 87%). LCMS (ESI) mass / charge: 414 (M + 1).

Example 109D

tert-Butyl-4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4- (hydroxymethyl) piperidine-1-carboxylate

To a mixture of Example 109C (350 mg, 0.85 mmol) and K ₂ CO ₃ (600 mg, 4.34 mmol) in DMSO (10 ml) was added dropwise 30% H ₂ O ₂ (10 ml) at 0 ° C. . After completion of the dropwise addition, the mixture was stirred at 25 ° C for 10 hours, and then diluted with water (50 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (50 ml × 2), brine (50 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound as yellow solids (270 mg, yield: 68%). LCMS (ESI) mass / charge: 432 (M + 1).

Example 109E

6-Fluoro-3- (4- (hydroxymethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 109D (100 mg, 0.23 mmol) in DCM (10 ml) and TFA (3 ml) was stirred at 25 ° C. for 3 hours. The resulting mixture was evaporated to give the title compound as a yellow oil, which can be was applied directly to the next step without further purification. LCMS (ESI) mass / charge: 332 (M + 1).

Example 109F

3- (1- (Cyclopropylmethyl) -4- (hydroxymethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 108E. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ ppm 0.06-0.35 (m, 2H), 0.44-0.70 (m, 2H), 0.81-1 14 (m, 1H), 1.57-2.01 (m, 1H), 2.05-2.47 (m, 1H), 2.57-2.98 (m, 1H), 3.08 -3.28 (m, 1H), 3.32-3.52 (m, 1H), 7.38-7.69 (m, 2H), 7.80 (s, 1H), 8.34 (s , 1H). LCMS (ESI) mass / charge: 386 (M + 1).

Example 110

Methyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -1- (cyclopropylmethyl) piperidine-4-carboxylate

Example 110A

1- (tert-Butyl) -4-methyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) piperidin-1,4 dicarboxylate

To a solution of Example 109A (250 mg, 0.52 mmol) in MeOH / DCM = 10/1 (1 ml) was added dropwise TMSCH ₂ N ₂ (0.52 ml, 1.04 mmol) at 0 ° C. in atmosphere N ₂ . After stirring at 0 ° C for 5 min, the reaction solution was quenched with HOAc / H ₂ O = 1/10 (20 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (50 ml × 2). The combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered and evaporated. The residue was purified by column chromatography to give the title compound (200 mg, yield: 78%). LCMS (ESI) mass / charge: 495, 497 (M, M + 2).

Example 10B

Methyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -1- (cyclopropylmethyl) piperidine-4-carboxylate

This example was obtained according to the method described in examples 109C-109F (11 mg, yield: 37%). LCMS (ESI) mass / charge: 414 (M + 1). ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.34 (d, J = 5.90 Hz, 2H), 0.67-0.75 (m, 2H), 0.99-1, 13 (m, 1H), 2.37 (br.s., 2H), 2.58 (br.s., 2H), 2.75 (d, J = 6.90 Hz, 2H), 2.89 -3.07 (m, 2H), 3.39-3.61 (m, 2H), 7.44 (dd, J = 8.09, 2.57 Hz, 1H), 7.75 (dd, J = 10.85, 2.57 Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) mass / charge: 414 (M + 1).

Scheme E

Example 111

3- (1- (Cyclopropylmethyl) -4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 111A

tert-butyl-4- (1-cyano-2-oxopropyl) -4-methylpiperidine-1-carboxylate

To a solution of Example 53C (5.0 g, 21.0 mmol) in dry THF (60 ml) was added dropwise LDA (26 ml, 52.0 mmol) at −78 ° C. under N ₂ , followed by dropwise addition of Ac ₂ O (5.4 g, 52.0 mmol) after stirring at -78 ° C for 1 h. The resulting mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was quenched sat. aq. NH ₄ Cl solution (30 ml). The aqueous layer was extracted with EtOAc (30 ml × 2). The combined organic layers were evaporated and the residue was purified by column chromatography to give the title compound (4.5 g, yield: 76.5%) as a yellow oil. LCMS (ESI) mass / charge: 281 (M + 1).

Example 111B

tert-Butyl-4- (1-cyano-2- (2- (2,6-dibromo-4-fluorophenyl) hydrazono) propyl) -4-methylpiperidine-1-carboxylate

A mixture of Example 111A (2.0 g, 7.14 mmol), HOAc (0.2 ml) and Example 1D (2.4 g, 8.57 mmol) in EtOH (30 ml) was stirred at 70 ° C. for 16 h. After removal of the solution in vacuo, the residue was purified by column chromatography to give the title compound (2.1 g, yield: 53.8%) as a light yellow solid.

Example 111C

tert-Butyl-4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -3-methyl-1H-pyrazol-4-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 111B (2.1 g, 3.84 mmol) and K ₂ CO ₃ (2.1 g, 15.4 mmol) in EtOH (30 ml) was heated to 80 ° C. and stirred for 4 hours. After removal of the solution under vacuum, the residue was purified by column chromatography to give the title compound (0.8 g, yield: 54.4%) as a light red solid.

Example 111D

tert-Butyl-4- (8-bromo-6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 111C (700 mg, 1.28 mmol), CuI (73 mg, 0.38 mmol), K ₃ PO ₄ (814 mg, 3.84 mmol) and N, N-dimethyl-1,2-ethane- 1,2-diamine (68 mg, 0.76 mmol) in DMF (15 ml) was stirred at 70 ° C for 5 hours in an atmosphere of N ₂ . After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (400 mg, yield: 67.0%) as a yellow solid. LCMS (ESI) mass / charge: 465, 467 (M, M + 2).

Example 111E

tert-Butyl-4- (8-cyano-6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

The mixture of example 111D (650 mg, 1.39 mmol), Zn (CN) ₂ (326 mg, 2.78 mmol), Pd ₂ (dba) ₃ (254 mg, 0.28 mmol), DPPF (309 mg, 0 , 56 mmol) and Zn (181 mg, 2.78 mmol) in DMF (8 ml) was stirred at 120 ° C for 3 h in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (450 mg, yield: 78.5%) as yellow solids. LCMS (ESI) mass / charge: 412 (M + 1).

Example 111F

tert-Butyl-4- (8-carbamoyl-6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

To the mixture of Example 111E (450 mg, 1.09 mmol) and K ₂ CO ₃ (906 mg, 6.56 mmol) in DMSO (10 ml) was added 30% H ₂ O ₂ (6 ml) at 0 ° C. After completion of the dropwise addition, the mixture was stirred at 25 ° C. for 16 hours, and then diluted with water (50 ml). The aqueous phase was extracted with EtOAc (50 ml × 2). The combined organic layers were washed with sat. aq. Na ₂ SO ₃ solution (50 ml × 2), brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (450 mg, yield: 95.7%) as white solids. LCMS (ESI) mass / charge: 430 (M + 1).

Example 111G

3- (1-Cyclopropylmethyl) -4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 109E and 109F. (50 mg, yield: 56.2%). ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.41 (d, J = 4.52 Hz, 2H), 0.64-0.83 (m, 2H), 1.12 (br. s., 1H), 1.47 (br.s., 3H), 2.09 (br.s., 2H), 2.50 (s, 3H), 2.54-2.71 (m, 2H) ), 2.84-3.29 (m, 4H), 3.52 (br.s., 2H), 7.28 (d, J = 8.03 Hz, 1H), 7.48-7.69 (m, 1H); 8.63 (br.s., 1H). LCMS (ESI) mass / charge: 384 (M + 1).

Example 112

3- (1-Ethyl-4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.20-1.61 (m, 6 N), 2.09 (br.s., 2H ), 2.49 (s, 3H), 2.52-2.77 (m, 2H), 3.17 (br.s., 4H), 3.49 (br.s., 2H), 7, 16-7.34 (m, 1H), 7.46-7.63 (m, 1H), 8.46 (s, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 113

6-Fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 0.84 (d, J = 6.5 Hz, 7H), 1.26 (s, 3H), 1, 76 (d, J = 6.8 Hz, 3H), 2.00 (d, J = 7.3 Hz, 2H), 2.13-2.29 (m, 3H), 2.34 (s, 1H ), 2.41 (s, 3H), 2.68 (s, 1H), 7.36 (dd, J = 2.5, 8.3 Hz, 1H), 7.55 (dd, J = 2, 5, 11.0 Hz, 1H), 8.04 (s, 1H), 8.29 (br.s. 1H), 10.63 (s, 1H). LCMS (ESI) mass / charge: 386 (M + 1).

Example 114

6-Fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) d ppm 1.34 (d, J = 5.52 Hz, 6H), 1.47 (br.s. , 3H), 2.11 (br.s., 2H), 2.51 (s, 3H), 2.53-2.72 (m, 2H), 3.11 (br.s., 2H), 3.44 (br.s., 3H), 7.20-7.38 (m, 1H), 7.59 (dd, J = 10.92, 2.64 Hz, 1H), 8.66 (br .s., 1H). LCMS (ESI) mass / charge: 372 (M + 1).

Example 115

3- (1,4-Dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.46 (s, 3H), 2.05 (br.s., 2H), 2.50 (s, 3H), 2.56 (d, J = 11.67 Hz, 2H), 2.79 (s, 3H), 3.09 (br.s., 2H), 3.34-3.41 (m, 2H), 7.31 (dd, J = 8.09, 2.32 Hz, 1H), 7.63 (dd, J = 10.98, 2.20 Hz, 1H), 8.55 ( s, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 116

6-Fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide

This example was obtained according to the method described in example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1.02-1.14 (m, 6H), 1.26 (s, 3H), 1.69-1 81 (m, 2H), 2.11-2.24 (m, 4H), 2.32-2.44 (m, 6H), 2.68 (br.s. 2H), 7.37 (dd , J = 2.5, 8.3 Hz, 1H), 7.56 (dd, J = 2.5, 11.0 Hz, 1H), 8.06 (s, 1H), 8.28 (s, 1H), 10.65 (s, 1H). LCMS (ESI) mass / charge: 402 (M + 1).

Example 117

3- (1-Ethyl-2,4-dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1.07 (t, J = 7.0 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 1.41 (s, 3H), 1.84-1.72 (m, 1H), 1.97 (d, J = 10.8 Hz, 2H), 2.05-2.16 (m, 1H), 2.44 (s, 3H), 2.54-2.70 (m, 2H), 2.77 (br.s. 1H), 2.90-3.03 (m, 2H ), 7.41 (dd, J = 2.4, 8.4 Hz, 1H), 7.55 (dd, J = 2.5, 11.0 Hz, 1H), 8.05 (s, 1H) 8.33 (s, 1H); 10.63 (s, 1H). LCMS (ESI) mass / charge: 372 (M + 1).

Example 118

3- (1-Ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.37-1.41 (t, 3H), 1.58 (s, 3H), 2.47-2 49 (m, 1H), 2.51 (s, 3H), 2.67-2.74 (m, 1H), 3.29-3.30 (m, 2H), 3.34-3.67 (m, 4H), 7.33-7.35 (d, 1H), 7.66-7.69 (d, 1H), 8.52 (bs, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 119

6-Fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.36-1.45 (m, 6H), 1.52-1.59 (m, 3H), 2 48 (s, 4H), 2.61-2.73 (m, 1H), 3.45-3.53 (m, 1H), 3.55-3.82 (m, 4H), 7.24 -7.33 (m, 1H), 7.56-7.68 (m, 1H), 8.40-8.55 (bs, 1H). LCMS (ESI) mass / charge: 358 (M + 1).

Example 120

3- (1- (Cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 0.59 (d, 2H), 0.96-1.06 (m, 1H), 1.53 (s , 3H), 2.12-2.22 (m, 1H), 2.48 (s, 5H), 2.83-2.94 (m, 1H), 2.98-3.08 (m, 2H ), 3.11-3.20 (m, 1H), 7.33-7.36 (m, 1H), 7.61-7.1H74 (m, 1H). LCMS (ESI) mass / charge: 370 (M + 1).

Example 121

3- (1,3-Dimethylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.74 (s, 3H), 2.37 (s, 3H), 2.94 (s, 3H), 4.27 (d, J = 9.79 Hz, 2H), 4.43 (d, J = 9.29 Hz, 2H), 7.29 (d, J = 8.28 Hz, 1H) 7.62 (d, J = 10.92 Hz, 1H); 8.51 (br.s., 1H). LCMS (ESI) mass / charge: 316 (M + 1).

Example 122

3- (1-Ethyl-3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.01-1.08 (w, 3H), 1.65-1.70 (m, 3H), 2 34 (s, 3H), 2.55-2.65 (m, 2H), 3.47-3.53 (m, 2H), 3.59-3.66 (m, 2H), 7.28 -7.36 (dd, 1H); 7.63-7.73 (dd, 1H). LCMS (ESI) mass / charge: 330 (M + 1).

Example 123

6-Fluoro-3- (1-isopropyl-3-methyl azetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.26 (d, J = 6.53 Hz, 6H), 1.75 (s, 3H), 2, 40 (s, 3H), 3.38 (d, J = 5.90 Hz, 1H), 4.20-4.28 (m, 2H), 4.33-4.44 (m, 2H), 7 27-7.43 (dd, 1H); 7.62-7.76 (dd, 1H); 8.43-8.58 (bs, 1H). LCMS (ESI) mass / charge: 344 (M + 1).

Example 124

3- (1- (Cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 0.46 (d, J = 4.02 Hz, 2H), 0.66-0.82 ( m, 2H), 1.09 (d, J = 6.02 Hz, 1H), 1.76 (s, 3H), 2.37 (s, 3H), 3.19 (br.s., 2H) 4.19-4.40 (m, 2H); 4.54 (d, J = 9.16 Hz, 2H); 7.24 (br.s., 1H); 7.57 (br.s. , 1H); 8.53 (br.s., 1H). LCMS (ESI) mass / charge: 356 (M + 1).

Example 125

6-Fluoro-3- (1- (2-hydroxy-2-methylpropyl) -3-methylazetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide

This example was obtained according to the method described in example 111. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.32 (s, 6H), 1.75 (s, 3H), 2.30-2, 43 (m, 3H), 3.24 (s, 2H), 4.35 (d, J = 9.91 Hz, 2H), 4.52 (d, J = 9.29 Hz, 2H), 7, 26 (d, J = 8.03 Hz, 1H); 7.61 (d, J = 11.04 Hz, 1H); 8.50 (br.s., 1H). LCMS (ESI) mass / charge: 374 (M + 1).

Example 126

6-Fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 126A

tert-Butyl-4- (1-cyano-2- (2- (2,6-dibromo-4-fluorophenyl) hydrazinyl) -2-oxoethyl) -4-methylpiperidine-1-carboxylate

A mixture of Example 105C (2.73 g, crude, 9.67 mmol), HATU (5.51 g, 0.26 mmol), Example 1D (3.29 g, 11.60 mmol) and Et ₃ N (2, 84 g, 29.01 mmol) in DMF (20 ml) was stirred at 25 ° C for 10 h in an atmosphere of N ₂ . After completion, the reaction mixture was quenched with water (100 ml) and extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (50 ml × 2) and brine (50 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (4.50 g, yield: 85%) as yellow solids.

Example 126B

tert-Butyl-4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -3-hydroxy-1H-pyrazol-4-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 126A (4.50 g, 8.21 mmol) and K ₂ CO ₃ (2.27 g, 16.42 mmol) in ethanol (100 ml) was stirred at 80 ° C. for 15 hours. After removing the solution under vacuum the residue was diluted with water (100 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were washed with water (50 ml × 2) and brine (50 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (3.81 g, yield: 84%) as a yellow solid.

Example 126C

tert-Butyl-4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -3-methoxy-1H-pyrazol-4-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 126B (2.3 g, 3.65 mmol), Mel (517.80 mg, 3.65 mmol) and K ₂ CO ₃ (1.51 g, 10.94 mmol) in DMF (50 ml) was stirred at 25 ° C for 15 hours. After removing the solution in vacuo, the residue was diluted with water (100 ml). The aqueous layer was extracted with EtOAc (100 ml × 2). The combined organic layers were digested with water (50 ml × 2), brine (50 ml × 2), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (590 mg, yield: 28.76%) as a yellow solid.

Example 126D

tert-Butyl-4- (8-bromo-6-fluoro-2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 126C (680 mg, 1.21 mmol), CuI (69 mg, 0.36 mmol), N ¹ , N ² -dimethylethan-1,2-diamine (64 mg, 0.73 mmol) and K ₃ PO ₄ (770 mg, 3.63 mmol) in DMF (15 ml) was stirred at 70 ° C for 10 hours in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (455 mg, yield: 78%) as white solids. LCMS (ESI) mass / charge: 481, 483 (M, M + 2).

Example 126E

tert-Butyl-4- (8-cyano-6-fluoro-2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

The mixture of example 126D (400 mg, 0.83 mmol), Zn (CN) ₂ (108 mg, 1.69 mmol), Pd ₂ (dba) ₃ (152 mg, 0.16 mmol), DPPF (185 mg, 0 , 33 mmol) and Zn (108 mg, 1.66 mmol) in DMF (8 ml) was stirred at 120 ° C for 15 h in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give the title compound (330 mg, yield: 81%) as yellow solids. LCMS (ESI) mass / charge: 428 (M + 1).

Example 126F

tert-Butyl-4- (8-carbamoyl-6-fluoro-2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-carboxylate

To the mixture of Example 126E (200 mg, 0.47 mmol) and K ₂ CO ₃ (300 mg, 2.17 mmol) in DMSO (5 ml) was added 30% H ₂ O ₂ (5 ml) at 0 ° C. After stirring at 25 ° C. for 15 hours, the mixture was diluted with water (50 ml). The aqueous layer was extracted with EtOAc (50 ml × 3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (195 mg, yield: 93%) as white solids. LCMS (ESI) mass / charge: 446 (M + 1).

Example 126G

6-Fluoro-2-methoxy-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A solution of Example 126F (100 mg, 0.22 mmol) in a DCM / TFA mixture (10 ml / 3 ml) was stirred at 25 ° C. for 3 hours. After removal of the solution under vacuum, the title compound was obtained and it was used directly in the next step no additional cleaning.

Example 126H

6-Fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of example 126G (78 mg, crude, 0.22 mmol), acetone (70 mg, 1.2 mmol) and Na (CN) BH ₃ (140 mg, 2.22 mmol) in a mixture of THF / MeOH (15 ml / 5 ml) was stirred at 24 ° C for 15 hours. The mixture was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (30 ml × 2). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (35 mg, yield: 41%) as a white solid. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.27-1.52 (m, 9 H), 1.77-2.19 (m, 2H), 2.69 (br.s. , 2H), 2.84-3.28 (m, .2H), 3.39-3.55 (m, 3H), 4.06 (s, 3H), 7.31 (dd, J = 8, 03, 2.51 Hz, 1H), 7.66 (dd, J = 10.98, 2.45 Hz, 1H), 8.55 (br.s., 1H). LCMS (ESI) mass / charge: 388 (M + 1).

Example 127

2- (Benzyloxy) -6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 127A

A mixture of Example 126B (3.0 g, 5.48 mmol), Boc ₂ O (10.0 g, 45.8 mmol) and DMAP (670 mg, 5.48 mmol) was stirred at 80 ° C. for 3 hours. After cooling to room temperature, the mixture was diluted aq. NaHCO ₃ solution (30 ml). The aqueous layer was extracted with DCM (100 ml × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound (4.5 g, crude), which could be used directly in the next step without further purification.

Example 127B

A mixture of Example 127A (4.5 g, 5.31 mmol) and K ₂ CO ₃ (1.46 g, 10.62 mmol) in MeOH (40 ml) was stirred at 20 ° C. for 4 hours. The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography to give the title compound (3.1 g, yield: 80%) as a yellow solid.

Example 127C

A mixture of Example 127B (2.5 g, 3.35 mmol), K ₂ CO ₃ (925 mg, 6.7 mmol) and BnBr (626 mg, 3.68 mmol) in MeOH (30 ml) was stirred at 60 ° C. for 8 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography to give the title compound (1.4 g, crude) as a white solid.

Example 127D

3- (Benzyloxy) -1- (2,6-dibromo-4-fluorophenyl) -4- (4-methylpiperidin-4-yl) -1H-pyrazol-5-amine

A solution of Example 127C (1.4 g, 1.63 mmol) in 4M HCl / EtOAc (20 ml) was stirred at 10 ° C. for 3 hours. After removing the solution under vacuum, the title compound (1.0 g, yield: 100%) was obtained as a yellow solid, and it was used directly in the next step without further purification.

Example 127E

tert-Butyl-4- (5-amino-3- (benzyloxy) -1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazol-4-yl) -4-methylpiperidin-1-carboxylate

A mixture of Example 127D (1.0 c 1.78 mmol), Et ₃ N (362 mc 3.56 mmol) and Boc ₂ O (776 mg, 3.56 mmol) in DCM (15 ml) was stirred at 10 ° C. within 4 hours. The mixture was diluted with H ₂ O (20 ml). The aqueous layer was extracted with DCM (15 ml × 2). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (1.0 g, crude) as a white solid.

Example 127F

2- (Benzyloxy) -6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

This example was obtained as described in examples 126D-126H. ¹ H NMR (400 MHz, DMSO-d ₆ ) 0.95 (d, J = 6.5 Hz, 6 H), 1.24 (s, 3H), 1.60-1.72 (m, 2H) 2.34 (br.s. 4H), 2.66-2.77 (m, 3H), 5.32 (s, 2H), 7.29-7.55 (m, 7H), 8, 04 (s, 1H), 8.34 (br.s. 1H), 10.20 (s, 1H). LCMS (ESI) mass / charge: 464 (M + 1).

Scheme F

Example 128

6-Fluoro-2- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

Example 128A

tert-Butyl 4- (2-pianoacetyl) piperidine-1-carboxylate

To a solution of acetonitrile (5.06 g, 123.4 mmol) in dry THF (200 ml) was added dropwise n-BuLi (39.5 ml, 98.6 mmol) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 2 hours. After this, a solution of 1- (tert-butyl) -4-methyl-piperidin-1,4-dicarboxylate (20 g, 82.2 mmol) in tetrahydrofuran (100 ml) dropwise added to the above mixture. After completion of the dropwise addition, the resulting mixture was heated to 15 ° C and stirred for 16 h, and then quenched with sat. aq. NH ₄ Cl solution (100 ml). The aqueous phase was extracted with EtOAc (100 ml × 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (7.9 g, yield: 38.1%) as a yellow solid. LCMS (ESI) mass / charge: 253 (M + 1).

Example 128B

tert-Butyl-4- (2-cyano-1- (2- (2,6-dibromo-4-fluorophenyl) hydrazono) ethyl) piperidine-1-carboxylate

A mixture of Example 128A (6.35 g, 25.16 mmol) and Example 1D (10 g, 35.2 mmol) in ethanol (80 ml) and HOAc (80 ml) was stirred at 85 ° C for 16 hours. After cooling to room temperature, the mixture was evaporated to give the title compound (15 g, crude), which could be used directly in the next step without further purification.

Example 128C

tert-Butyl-4- (5-amino-1- (2,6-dibromo-4-fluorophenyl) -1H-pyrazol-3-yl) piperidine-1-carboxylate

A mixture of Example 128B (13 g, 25.1 mmol) and Et ₃ N (12.7 g, 125.5 mmol) in ethanol (100 ml) was heated to 80 ° C. for approximately 16 hours. After cooling to room temperature, the mixture evaporated. The residue was purified by column chromatography to give the title compound (11 g, yield: 84.6%) as a yellow solid.

Example 128D

tert-Butyl-4- (8-bromo-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-2-yl) piperidine-1-carboxylate

A mixture of Example 128C (1.5 g, 2.9 mmol), CuI (166 mg, 0.87 mmol), K ₃ PO ₄ (1.8 g, 8.7 mmol) and N ¹ , N ² -dimethylethanes 1,2-diamine (153 mg, 1.74 mmol) in DMF (8 ml) was stirred at 55 ° C for 18 h in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was diluted with water (20 ml). The aqueous layer was extracted with EtOAc (20 ml × 2). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography to give the title compound (350 mg, yield: 27.6%) as a yellow solid. LCMS (ESI) mass / charge: 437, 439 (M, M + 2).

Example 128E

tert-Butyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-2-yl) piperidine-1-carboxylate

The mixture of example 128D (350 mg, 0.8 mmol), Zn (CN) ₂ (188 mg, 1.6 mmol), Pd ₂ (dba) ₃ (110 mg, 0.12 mmol), DPPF (133 mg, 0 , 24 mmol) and powdered Zn (104 mg, 1.6 mmol) in DMF (4 ml) was stirred at 120 ° C for 2 h in an atmosphere of N ₂ . After cooling to room temperature, the resulting mixture was filtered and the filtrate was evaporated. The residue was purified by preparative TLC to give the title compound (50 mg, yield: 16.2%) as a yellow solid. LCMS (ESI) mass / charge: 402 (M + 1).

Example 128F

6-Fluoro-2- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixed solution of Example 128E (50 mg, 0.125 mmol) in TFA (1 ml) and DCM (6 ml) was stirred at 20 ° C. for 2 hours. The resulting mixture was evaporated. The residue was purified by preparative HPLC to give the title compound (23 mg, yield: 59.0%) as a white solid. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.07-1.27 (m, 9H), 2.51 (d, J = l, 51 Hz, 2H), 2.76-2, 97 (m, 2H), 3.34 (d, J = 3.26 Hz, 2H), 5.74 (br.s., 1H), 7.36-7.39 (m, 1H), 7, 68-7.72 (m, 1H). LCMS (ESI) mass / charge: 302 (M + 1).

Example 129

2- (1-Ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide

A mixture of Example 128F (20 mg, 0.066 mmol), 40% acetaldehyde (0.2 ml) and Na (CN) BH ₃ (17 mg, 0.264 mmol) in MeOH (5 ml) was stirred at 10 ° C for 16 hours. After completion of the reaction, the resulting mixture was diluted with water (5 ml). The aqueous layer was extracted with DCM (20 ml × 2). The combined organic layers were evaporated. The residue was purified by preparative HPLC to give the title compound (17.36 mg, yield: 78.9%) as a pale yellow solid. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ ppm 1.38 (t, J = 7.28 Hz, 3H), 1.98-2.23 (m, 2H), 2.28-2, 49 (m, 2H), 2.92-3.25 (m, 5H), 3.57 (d, t = 11.54 Hz, 2H), 5.83 (s, 1H), 7.29 ( dd, J = 8.28, 2.51 Hz, 1H), 7.61 (dd, J = 10.92, 2.51 Hz, 1H), 8.60 (br.s., 1H). LCMS (ESI) mass / charge: 330 (M + 1).

In vitro studies

Cell PAR Assay

HCC1937 cells were seeded in 96-well plates at 4 × 10 ⁴ cells / well and incubated at 37 ° C. in an incubator overnight. After treatment with the test compound for 30 minutes, the cells were treated with 1 mM H ₂ O ₂ for 10 minutes. The cells were washed twice with 200 μl of pre-chilled PBS and fixed with 100 μl of a pre-chilled mixture of methanol / acetone (7: 3) on ice for 30 min After air drying, the plates were blocked using a PBS-Tween blocking solution (0.05%) with dissolved 5% skimmed milk powder for 30 minutes at room temperature.

Cells were incubated with 10H antibody to PAR (1: 100) at room temperature for 1 hour, followed by 3 times washing with PBS-Tween20; and then added to a blocking solution containing fluorescein conjugated isothiocyanate (FITC) goat secondary anti-mouse antibody and 1 μg / ml DAPI for incubation without access of light at room temperature for 1 hour. After washing 3 times with PBS-Tween20, the plates were analyzed using a fluorescent microplate reader (Flexstation III, Molecular Devices).

Enzymatic PARP assay (following Universal Colorimetric PARP1 Assay HT assay kit instructions).

A 96-well plate was coated with histone proteins and incubated overnight at 4 ° C. After washing 3 times with 200 μl of PBST solution, the plate was blocked with a blocking solution and incubated for 30 min at room temperature, and then washed 3 times with PBST solution. The compound to be tested was processed and added to the plate. Thereafter, 20 μl of a diluted solution of PARP1 (1HM) or 20 μl of PARP2 (3 nM) was added to the reaction system and incubated for 1 or 2 hours. 50 μl of the streptavidin-HRP mixture (1:50) was added to the plate and incubated for 30 min at room temperature. Then, the plate was washed three times with PBST buffer. 100 μl (HRP) (chemiluminescent substrate A and substrate B (1: 1)) was added to the plate and the plate was immediately read using a microplate reader (Envision, PerkinElmer).

Antiproliferation Assay

Cells MDA-MB-436 and MDA-MB-231 were plated in 96-well plates with a density of 500 and 2000 cells per well, respectively, and cultured overnight in RPMI1640 medium supplemented with 10% (v / v) FBS and 1% (v / v) penicillin-streptomycin. After adding the compound to be tested, the cells were treated for 8 days. Cell viability values were measured using a CCK8 kit and then using a specific method: adding 10 μl of CCK8 reagent to each well and incubating for 3 hours at 37 ° C in an incubator with 5% CO ₂ . After shaking for 10 min, the absorbance values (OD) were measured at 450 nm using Flexstation III (Molecular Devices).

To test the combination of compounds (in combination with drugs for DNA damage), a PF ₅₀ value was calculated to measure the synergistic effect of the drug. PF ₅₀ = [IC _{50 of the} test compound] / [IC _{50 of the} test compound with a fixed concentration of the drug for DNA damage]. In this study, temozolomide (TMZ) was used as a drug for DNA damage.

These enzymatic inhibition of PARP-1 IC ₅₀ and cell PAR-PEGylation _EC50 compounds of the present invention are shown in Table I below. Compounds with an IC ₅₀ value of from 1 nM to 100 nM were designated as +++; compounds with an IC ₅₀ value of from 101 nM to 1000 nM were designated as ++ and compounds with an IC ₅₀ value above 1000 nM were designated as +.

Claims (176)

1. The compound of formula (I) or its pharmaceutically acceptable salt:

Where D represents —C (R _d1 ) (R _d2 ) - or —N (R _d4 ) -; R _{1 is} selected from the group consisting of H, C _1-3 alkyl, C _1-3 alkyloxy, benzyloxy and

wherein R _{101 is} selected from the group consisting of H, methyl, ethyl, n-propyl or isopropyl; R ₃ selected from the group comprising H, F, Cl, Br; R ₂ satisfies any of the following requirements (1) to (10): (1) R _{2 is} selected from H or CN; (2) R ₂ is —CH ₂ N (R ₂₀₁ ) (R ₂₀₂ ), wherein R ₂₀₁ and R _{202 are} individually and independently selected from the group consisting of H, C _1-3 alkyl, C _1-3 alkylacyl, or C _3-6 cycloalkylacyl; (3) R ₂ selected from the group including

,

in which R ₂₀₃ , R ₂₀₄ , R ₂₁₇ and R _{218 are} individually and independently selected from the group consisting of H, substituted or unsubstituted C _1-3 alkyl, cyclopropyl or cyclopropylmethylene, the substituent is selected from the group consisting of OH and methyl, and the number of substituents is 0, 1, 2 or 3; R _{219 is} selected from the group consisting of methyl and ethyl; (4) R ₂ selected from

in which R ₂₀₅ and R _{206 are} individually and independently selected from the group consisting of H, unsubstituted C _1-3 alkyl; R _{206 is} also selected from the group consisting of OH; (5) R ₂ selected from

wherein R _{207 is} selected from the group consisting of H, substituted or unsubstituted C _1-3 alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, oxacyclobutyl or oxacyclobutylalkylene, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , and methylsulfonyl, and the number of substituents is 0, 1, 2, or 3; (6) R ₂ selected from the group including

or

in which R _{208 is} selected from the group consisting of H, cyclopropylmethylene, unsubstituted C _1-4 alkyl and cyclobutyl; (7) R ₂ selected from

wherein R _{209 is} selected from the group consisting of —N (R _d4 ) - or —O—; (8) R ₂ selected from

wherein R _{210 is} selected from the group consisting of NH ₂ , N, N-di (C _1-3 alkyl) amino and C _1-3 alkylamino; (9) R ₂ selected from

in which R _211-213 selected from the group consisting of H or substituted or unsubstituted C _1-4 alkyloxycarbonyl, C _1-4 alkyl and CN, R _{214 is} selected from the group consisting of H or substituted or unsubstituted C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkylmethylene, tetrahydro-2H-pyran,

or

where the substituent is R ₂₁₅ , R _{215 is} selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , methyloxy, ethyloxy, methylsulfonyl, ethylsulfonyl, methyloxycarbonyl, ethyloxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl, the amount of R ₂₁₅ is 1, 2 or 3, (10) R ₂ selected from

in which T _{22 is} selected from the group comprising N or C (R ₂₂₄ ), R _{220-224 is} separately and independently selected from the group comprising H, F, Cl, Br, I, C _1-3 alkylamino-C _1-3 alkyl and

; R _d1 and R _{d2 are} separately and independently selected from the group consisting of H, F, Cl, Br, I, OH; R _{d4 is} selected from the group consisting of H and R ₀₃ ; R ₀₃ represents C _1-10 alkyl; R _{03 is} optionally substituted with R ₀₀₁ ; R _{001 is} selected from the group consisting of F, Cl, Br, I, OH, N (CH ₃ ) ₂ , NH (CH ₃ ), NH ₂ , and CH ₃ O; and the amount of R _{001 is} selected from 0, 1, 2, and 3. 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein D is selected from —NH—, —N (CH ₃ ) -, —C (F) ₂ -, —C (H) (F) - and —C ( H) (OH) -. 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _{2 is} selected from —CH ₂ N (R ₂₀₁ ) (R ₂₀₂ ), wherein R ₂₀₁ and R _{202 are} separately and independently selected from the group consisting of H and cyclopropylacyl. 4. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from the group including

and

in which R _{203 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, -CH ₂ C (CH ₃ ) (CH ₃ ) (OH) and cyclopropylmethylene, R _{204 is} selected from the group consisting of methyl, ethyl, n -propyl and isopropyl, R _{217-219 are} separately and independently selected from the group consisting of methyl and ethyl. 5. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

in which R _{205 is} selected from the group consisting of H, methyl, ethyl, n-propyl and isopropyl, R _{206 is} selected from the group consisting of H and OH. 6. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

in which R _{207 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ S ( = O) ₂ CH ₃ , -CH ₂ CH ₂ CN,

and

. 7. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from the group including

or

in which R _{208 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene and cyclobutyl. 8. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

in which R ₂₀₉ represents O. 9. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

in which R _{210 is} selected from the group consisting of dimethylamino, methylamino and NH ₂ . 10. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

, wherein R _{211 is} selected from the group consisting of H, CN, methyl, ethyl, hydroxylmethyl and methyloxycarbonyl, R _{212 is} selected from the group consisting of H and methyl, R ₂₁₃ represents H, R _{214 is} selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CH ₂ C (OH) (CH ₃ ) ₂ , —CH ₂ C (F) ( CH ₃ ) ₂ , —CH ₂ CH ₂ F, —CH ₂ CF ₃ , —CH ₂ CH ₂ CF ₃ , —CH ₂ CH ₂ NH ₂ , —CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , - CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) ₂ , -S (= O) ₂ CH ₃ , -CH ₂ CH ₂ S (= O) ₂ CH ₃ ,

cyclopropyl cyclopropylmethylene

11. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from

in which T _{22 is} selected from the group comprising N or C (R ₂₂₄ ), R _{220-224 is} separately and independently selected from the group comprising H, F, Cl, Br, I, C _1-3 alkylamino-C _1-3 alkyl and

; C _1-3 alkylamino-C _1-3 alkyl selected from methylaminomethylene. 12. The compound or its pharmaceutically acceptable salt according to claim 1, where R ₂ selected from the group including

13. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group including 1) 6-fluoro-3- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 2) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 3) 6-fluoro-3- (1- (2-fluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 4) 3- (1-cyclopropylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 5) 3- (1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 6) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 7) 6-fluoro-3- (1- (2-fluoro-2-methylpropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 8) 3- (1- (cyclopropanecarbonyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 9) 6-fluoro-3- (1-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 10) 6-fluoro-3- (1-isopropylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 11) 6-fluoro-3- (1- (oxetan-3-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 12) 6-fluoro-3- (1-propylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 13) 3- (1- (2-aminoethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 14) 3- (1- (2- (dimethylamino) ethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 15) 6-fluoro-3- (1- (2-methoxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 16) 6-fluoro-3- (1- (2-hydroxyethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 17) 3- (1-ethylpiperidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 18) 3- (1-ethylazepan-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 19) 6-fluoro-3- (1-methylazepan-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 20) 6-fluoro-3- (1-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 21) 3- (1-ethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 22) 6-fluoro-3- (1-isopropylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 23) 6-fluoro-3- (pyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 24) 6-fluoro-3- (1-propylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 25) 6-fluoro-3- (1-methylpyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 26) 3- (1-ethylpyrrolidin-2-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 27) 3- (1-ethylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 28) 6-fluoro-3- (3-methyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 29) 3- (3-ethyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 30) 3- (3-cyclobutyl-3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 31) 3- (3- (cyclopropylmethylene) -3-azabicyclo [3.1.0] hexan-1-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide; 32) 6-fluoro-3- (3-isopropyl-3-azabicyclo [3.1.0] hexan-1-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 33) 3- (3-azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 34) 3- (3-ethyl-3-azabicyclo [3.1.0] hexan-6-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 35) 3- (8-ethyl-8-azabicyclo [3.2.1] octan-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 36) 6-fluoro-3- (4-hydroxypyrrolidin-2-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 37) 3-cyano-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 38) 3-cyano-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 39) 3- (aminomethyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 40) 3- (cyclopropanecarboxamidomethylene) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 41) 6-fluoro-3- (4-fluorophenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 42) 6-fluoro-3- (2-fluoro-4 - ((methylamino) methylene) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 43) 6-fluoro-3- (4 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 44) 6-fluoro-3- (2-fluoro-5 - ((methylamino) methyl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 45) 6-fluoro-3- (pyridin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 46) 6-fluoro-3- (4- (piperidin-3-yl) phenyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 47) 6-fluoro-3- (tetrahydro-2H-pyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 48) 3- (4- (dimethylamino) cyclohexyl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 49) 6-fluoro-3- (4-methylpiperazine-1-carbonyl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 50) 3- (1- (cyclopropylmethyl) piperidin-4-yl) -4,4,6-trifluoro-4H-pyrazolo [1,5-a] indole-8-carboxamide; 51) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4-hydroxy-4H-pyrazolo [1,5-a] indole-8-carboxamide; 52) 3- (1-ethylpiperidin-4-yl) -6-fluoro-4-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 53) 6-fluoro-3- (4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 54) 3- (1-ethyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 55) 3- (1-cyclopropyl-4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 56) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide; 57) 3- (1- (cyclopropylmethylene) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 58) 3- (1- (4,4-difluorocyclohexyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 59) 6-fluoro-3- (4-methyl-1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide; 60) 6-fluoro-3- (1- (2-fluoroethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 61) 6-fluoro-3- (4-methyl-1- (2,2,2-trifluoroethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide; 62) 6-fluoro-3- (4-methyl-1- (3,3,3-trifluoropropyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide; 63) 3- (1 - ((1-cyanocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 64) 3- (1 - ((1-cyanocyclobutyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 65) 6-fluoro-3- (4-methyl-1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide; 66) 6-fluoro-3- (4-methyl-1 - ((tetrahydro-2H-pyran-4-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2- b] pyrazole-8-carboxamide; 67) 3- (1 - ((1-aminocyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 68) 6-fluoro-3- (4-methyl-1- (oxetan-3-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 69) 6-fluoro-3- (1- (2-methoxyethyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 70) 6-fluoro-3- (1 - ((1-hydroxycyclopropyl) methyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 71) 6-fluoro-3- (4-methyl-1 - ((3-methyloxetan-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 72) 6-fluoro-3- (1- (3-methoxypropyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 73) 6-fluoro-3- (4-methyl-1 - ((1- (methylsulfonyl) cyclopropyl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide; 74) 6-fluoro-3- (4-methyl-1- (thiazol-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 75) 6-fluoro-3- (4-methyl-1- (methylsulfonyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 76) 6-fluoro-3- (1- (3-fluorocyclobutyl) -4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 77) 6-fluoro-3- (4-methyl-1- (thiophen-2-ylmethyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 78) 3- (1 - ((1-ethylpiperidin-4-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole -8-carboxamide; 79) 6-fluoro-3- (4-methyl-1 - ((1-methylazetidin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 80) ethyl-2 - ((4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -4-methylpiperidin-1-yl) methyl) cyclopropanecarboxylate; 81) 3- (1 - ((2- (dimethylcarbamoyl) cyclopropyl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide; 82) 6-fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 83) 6-fluoro-3- (4-methyl-1 - ((4-methylthiazol-5-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 84) 6-fluoro-3- (4-methyl-1 - ((1-methyl-1H-imidazol-2-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [1, 2-b] pyrazole-8-carboxamide; 85) 3- (1 - ((1,2-dimethyl-1H-imidazol-5-yl) methyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1 , 2-b] pyrazole-8-carboxamide; 86) 3- (1'-ethyl-4-methyl- [1,4'-bipiperidin] -4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole- 8-carboxamide; 87) 6-fluoro-3- (4-methyl-1 - ((6-oxo-1,6-dihydropyridazin-3-yl) methyl) piperidin-4-yl) -4H-benzo [4,5] imidazo [ 1,2-b] pyrazole-8-carboxamide; 88) 3- (1- (2-cyanoethyl) -4-methylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 89) 6-chloro-3- (1-ethyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 90) 3- (1-ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 91) 3- (1,3-dimethylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 92) 6-fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 93) 3- (1- (cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 94) 6-fluoro-3- (3-methyl-1- (oxetan-3-yl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 95) 6-fluoro-3- (1- (2-fluoroethyl) -3-methylpyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 96) 3- (1 - ((2,2-difluorocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide; 97) 6-fluoro-3- (3-methyl-1- (2,2,2-trifluoroethyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide; 98) 6-fluoro-3- (3-methyl-1- (2- (methylsulfonyl) ethyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8- carboxamide; 99) 6-fluoro-3- (3-methyl-1- (3,3,3-trifluoropropyl) pyrrolidin-3-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazol-8 β-carboxamide; 100) 3- (1 - ((1-aminocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 101) 3- (1 - ((1-cyanocyclobutyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 102) 3- (1 - ((1-cyanocyclopropyl) methyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide ; 103) 3- (1- (2-cyanoethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 104) 3- (1- (cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 105) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 106) 6-fluoro-3- (4-methyl-1,1-dioxo-2H-thiopyran-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 107) 3- (1,4-diethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 108) 3- (4-cyano-1- (cyclopropylmethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 109) 3- (1- (cyclopropylmethyl) -4- (hydroxymethyl) piperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 110) methyl 4- (8-carbamoyl-6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazol-3-yl) -1- (cyclopropylmethyl) piperidine-4-carboxylate; 111) 3- (1- (cyclopropylmethyl) -4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 112) 3- (1-ethyl-4-methylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 113) 6-fluoro-3- (1-isobutyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 114) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 115) 3- (1,4-dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 116) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -4-methylpiperidin-4-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 117) 3- (1-ethyl-2,4-dimethylpiperidin-4-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 118) 3- (1-ethyl-3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 119) 6-fluoro-3- (1-isopropyl-3-methylpyrrolidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 120) 3- (1- (cyclopropylmethyl) -3-methylpyrrolidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 121) 3- (1,3-dimethylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 122) 3- (1-ethyl-3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 123) 6-fluoro-3- (1-isopropyl-3-methylazetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 124) 3- (1- (cyclopropylmethyl) -3-methylazetidin-3-yl) -6-fluoro-2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 125) 6-fluoro-3- (1- (2-hydroxy-2-methylpropyl) -3-methylazetidin-3-yl) -2-methyl-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 126) 6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -2-methoxy-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 127) 2- (benzyloxy) -6-fluoro-3- (1-isopropyl-4-methylpiperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 128) 6-fluoro-2- (piperidin-4-yl) -4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide; 129) 2- (1-ethylpiperidin-4-yl) -6-fluoro-4H-benzo [4,5] imidazo [1,2-b] pyrazole-8-carboxamide. 14. The use of the compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-13 for the treatment of cancer. 15. A therapeutic agent for cancer, containing the compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-13.